Anatomy & Physiology for Midwives 3: Third Edition

Chapter 3. Endocrinology

Learning objectives

• To introduce the terminology used within endocrinology.

• To define the different types of hormones, their functions, main sites of production and mechanism of effects.

• To describe the role of the sex steroids.

• To relate endocrinology to the physiological process of reproduction.

Introduction

This chapter presents an overview of endocrinology and summarizes the role of hormones in the regulation of human physiology. Throughout the chapter, links to reproductive physiology will be highlighted and referenced to other chapters in the book where the relevant interactions will be described more specifically.

The endocrine system, in conjunction with the nervous system, coordinates, regulates and adjusts the internal physiology in response to changes in the external environment. The nervous system tends to react in situations where an immediate response is required, whereas the endocrine system is involved in sustaining body functions over a longer period (Table 3.1). For example, shivering is induced by neuromuscular activity to counteract a drop in the environmental temperature, whereas many body cycles, such as the menstrual cycle, are almost entirely orchestrated through hormonal systems. However, the two systems interact with each other and so some rapid responses have a hormonal component. For instance, the release of adrenaline, the fear–fight–flight reflex and hormonal release are often regulated by a neuronal pathway via the hypothalamus. The advantage of the endocrine system over the nervous system is that it can instigate a much more diffuse response in all body tissues at about the same time and coordinate integrated responses.

Chapter case study

Zara is now just 6 weeks pregnant. She feels concerned about feeling increasingly nauseated, especially late in the evening; she actually vomited last night. Zara rings you, as her midwife, the next day expressing her concern, especially as her sister has told her that this is not the typical morning sickness of pregnancy.

• What explanations could you give Zara to the likely cause of her nausea and what advice should you give her to help her cope with her nausea?

• How is nausea and vomiting of pregnancy differentiated from hyperemesis gravidarum?

• What are the possible complications of hyperemesis and what specific treatment is required to minimize complications?

Later on in her pregnancy, Zara has a routine appointment at about 26 weeks gestation with her midwife who undertakes routine urinalysis and discovers that Zara has glucosuria.

• What are the possible causes for this, what further investigations need to be undertaken and what advice and treatment may be required?

What is endocrinology?

The endocrine system originally appeared to be a relatively simple system of discrete glands (Fig. 3.1) that secreted chemical messengers, or hormones, into the blood where they would be carried to specific target cells at a distant site, inducing a reaction. However, it is now clear that the endocrine system is more complex. Some hormones are secreted into ducts and not into blood; for instance, androgens are secreted into the seminiferous tubules. Some organs that have other functions also produce hormones. For instance, the atrium of the heart produces atrial natriuretic peptide (ANP), which inhibits reabsorption of sodium chloride in the kidneys and hence affects blood pressure. Some hormones are produced by several different glands, for instance somatostatin, which is produced by the hypothalamus, pancreas, stomach and intestine. Although the trophoblast is the prime site of human chorionic gonadotrophin (hCG) production, it can also be produced by other tissues, albeit in very low concentrations (Iles and Chard, 1991). The placenta appears to be capable of synthesizing a very broad range of hormones and releasing factors that interact with both maternal and fetal physiology. Some substances such as noradrenaline can act as both hormone and neurotransmitter depending on their mode of delivery and whether they are released from a gland or from a nerve. The hypothalamus produces neurohormones that are important in the interaction between the endocrine and nervous systems.

Overall, the endocrine system (in partnership with the neural system) has the following functions:

• coordinates the homeostatic balance

• regulates various physiological systems such as the digestive system and reproductive system

• facilitates differentiation of the sexes in the embryonic stage and the manifestation of the secondary sexual characteristics at puberty

• modifies and induces behavioural changes within the individual.

The evolution of endocrinology

The evolution of the endocrine system has its rudiments within the activity of single-cell (unicellular) organisms. The unicellular organisms developed the ability to be attracted to chemicals, described as a chemotactic response, or to chemicals that were vital for the functioning of the organism, described as a chemotrophic response. Equally, these organisms developed the ability to recognize noxious chemicals (toxins) and were thus able to avoid them. The cell reacting to chemical signals interacting with receptor sites upon the cell membrane and within the cytoplasm led to the development of active mobility.

As multicellular organisms developed, the group of unicellular organisms that were the prototypes of multicellular organisms evolved chemical communication as an extension of the chemotrophic response. As multicellular evolution progressed further, the cells became more differentiated and specialized. Regulation therefore became the function of more specialized types of cells. This is reflected in the developmental sequence of a fetus, beginning with the division of a single cell (see Chapter 7). With each successive division, the resulting cells are slightly different from the original zygote cell (although differentiation during the initial divisions may be induced by the presence of maternally derived factors within the cytoplasm of the zygote). Although this differentiation is primarily under genetic control, it is achieved through a process of induction from chemical signals produced by one cell type that influence the division of other neighbouring cells. The altered gene expression of the dividing cells results in a changed morphology and developmental pathway.

As organisms became larger and more complex, cell-to-cell communication became more complicated. It evolved in two ways: the endocrine system (of chemical transmission via the circulating blood system) and the neural system (via transmission of an action potential; see Chapter 1). Under the traditional approach to biological science, the endocrine and neural systems were always considered in isolation; however, they are now considered to be extensions of the same system that are highly interactive. Many endocrine responses are initiated by a neuronal influence. Many neurotransmitters and neuromodulators have also been found to be endocrine hormones.

Classification of hormones

Hormones regulate metabolism, activate or inhibit the immune system, stimulate or inhibit growth, induce or suppress apoptosis (see below) and prepare the body to respond (such as fleeing or fighting) or undergo transition to a new stage of life such as puberty, pregnancy or the menopause. Hormones are produced by almost every organ and type of tissue; they function as cellular messengers. The action of hormones depends on the responses of the target cells and the pattern of hormonal secretion. Endocrine means ‘secreted inwards’ and is applied to hormones that fit the classical description of being secreted into the bloodstream and having an effect at a distant target. There are also exocrine hormones, which are ‘secreted outwards’ into ducts. These include hormones that are secreted into the vas deferens and uterine tubes.

A number of hormones have a local or paracrine effect, diffusing short distances to act on neighbouring cells or cells separated only by an intracellular space. Examples of a paracrine response are the effects of testosterone and anti-Müllerian hormone (AMH; also known as Müllerian-inhibiting hormone or substance, MIH or MIS) on sexual differentiation (see Chapter 5). If the hormone produced acts upon the same cell that produced it, it is described as autocrine. For example, an autocrine hormone may induce cellular division or signal the programmed death of the cell (apoptosis). If it affects adjacent cells and has a very localized action, it is described as a juxtacrine hormone. Therefore, the effect of a hormone depends on how and where it is secreted, the mode of transport (e.g. whether it is soluble or carried by a binding protein) and how quickly it is metabolized or inactivated.

Neuroendocrine hormones are synthesized in specialized neurons, and their effects can also be paracrine in nature (these are usually described as neurotransmitters and neuromodulators). Oxytocin is an example of a neuroendocrine hormone. It is released from the posterior lobe of the pituitary gland and influences the contractility of the myometrium (see Chapter 13) and myoepithelial cells in the breast (see Chapter 16). In these respects, oxytocin has an endocrine effect, but in many mammals it also modifies female behaviour by inducing parental behaviour in the presence of the sex steroids (Insel, 1992). Oxytocin is thought to influence the successful transition to parenthood in different ways; maternal behavioural changes tending to influence affectionate behaviour and emotional bonding and paternal parenting behaviour tending to affect play and social interaction with their infants (Gordon et al., 2010).

A pheromone is a hormone produced by an individual that induces a response, usually social, within another member of the same species. Releaser pheromones stimulate rapid behavioural responses such as attracting potential mates. Primer pheromones act via the olfactory and neuroendocrine system to produce delayed responses which are usually developmental. Receptors for pheromones are found on the vomeronasal organ close to the nasal cavity of mammals, which use pheromones to indicate identity of kin or family territory. It is controversial as to whether the human vomeronasal organ retains a function; some scientists think it is involved in social behaviour such as pair bonding, parental attachment, sexual attraction and synchrony of menstrual cycles (Halpern and Martinez-Marcos, 2003). The synchronization of menstrual cycles within a group of women, responses between lactating women and their offspring and female responses to non-odorants in male perspiration are suggested to be examples of pheromone effects in humans (Bhutta, 2007).

Secretion of hormones is influenced by a number of factors, including the nervous system, hormone-binding proteins, plasma concentrations of nutrients and ions, environmental changes and other hormones, such as stimulating and releasing hormones.

Hormones can be classified according to their structure (see Table 3.2). Steroid hormones and eicosanoids (the prostaglandin family of hormones) are lipids. The other classes are protein and peptide hormones and monoamines.

Steroid hormones

The steroid group of hormones consists of the sex steroids (progestagens, androgens and oestrogens), the glucocorticoids, mineralocorticoids, thyroid hormones and 1,25-dihydroxyvitamin D₃. Steroid hormones are derived from cholesterol which is synthesized from acetate (Fig. 3.2). As well as being the precursor for the steroid hormones, cholesterol is also an important structural component of cell membranes, providing rigidity.

The first and common step in the biosynthesis of sex steroids is the formation of pregnenolone, which is rate-limiting, and therefore important in controlling production of sex steroids. Pregnenolone is produced on the inner mitochondrial membrane whereas the next stages take place in the smooth endoplasmic reticulum (SER).

The three classes of sex steroids are structurally related, which offers the opportunity for interconversion. This means that a genetic defect in one of the steps can result not only in a deficiency of the normal amount of the product but also in an excess of another sex steroid. For instance, a genetic deficiency of the enzyme that converts 17α-hydroxyprogesterone to the precursor of cortisol results in increased levels of 17α-hydroxyprogesterone, which is converted into androstenedione and then into androgens. The unusually high level of androgens can cause masculinization of the female fetus. These structural similarities mean that the steroid hormones can affect the activity of other steroid hormones by exerting agonistic and antagonistic properties at the receptor level (see below). However, the effects of the hormones vary depending on their structure (see Table 3.3).

The main role of androgens is in the development and maintenance of masculine characteristics and fertility. Similarly, the dominant role of oestrogens is in development and maintenance of feminine characteristics and fertility. The key role for progesterone is the preparation for pregnancy and its maintenance. However, all the steroid hormones are produced in men and women but with varying profiles; therefore, for instance, men produce more androgens than women but also produce some oestrogen. Although androgens are primarily associated with the development and maintenance of male sex characteristics, they also affect sexual behaviour in women (Johnson, 2007).

As steroid hormones are lipid-soluble, they are able to diffuse freely across the cell membrane and have their effect within the target cell. In the cytoplasm, the steroid hormones may be altered. The receptor sites for thyroid hormone and the sex steroids are within the nucleus. Specific receptors for the other steroid hormones are within the cytoplasm; binding usually results in cleavage of smaller ‘heat-shock’ proteins from the receptors. Steroid hormones exert their effect by altering ribonucleic acid (RNA) synthesis and subsequent protein synthesis (Box 3.1). The steroid-receptor ligand binds to specific segments of DNA, steroid response elements (SRE) in promoter regions of the gene in that section of DNA, affecting the rate of transcription and gene expression. Protein synthesis can be increased (or decreased) within 30 min, and the effects of steroid hormones are therefore relatively slow in action compared with those of protein hormones. The term ‘anabolic steroids’ describes the effect of steroid hormones in influencing new tissue growth.

Box 3.1

Action of steroid hormones

• Transported in plasma bound to binding protein

• Hormone released and diffuses into target cell

• Hormone diffuses into nucleus

• Binds to specific receptor

• Affects DNA transcription

• Affects mRNA synthesis

• Affects protein synthesis

• Altered functional response of cell

The other class of lipid hormones is the eicosanoids (prostaglandins and leukotrienes) which have an important role in reproduction. Eicosanoids are formed from an arachidonic acid precursor, generated by the activity of either phospholipase C or phospholipase A₂ (Fig. 3.3). Arachidonic acid production appears to be the rate-limiting step. Phospholipase A₂ is present in an inactive form in lysosomes in cells that are released if the cell membranes become unstable. Most tissues of the body including the myometrium, cervix, ovary, placenta and fetal membranes synthesize prostaglandins. They have a short half-life and are metabolized quickly. They have an important role in amplifying signals at the onset of labour (see Chapter 13). Leukotrienes are also synthesized from arachidonic acid by the enzyme 5-lipoxygenase in leukocytes and macrophages. They are involved in inflammatory reactions particularly in asthma and allergy and also seem to be important in pregnancy.

Protein and peptide hormones bind to receptors located on or within the cell membrane. They initiate plasma membrane depolarization and a cascade of second-messenger systems and chemical changes within the cytoplasm, generating a faster response than steroid hormones. They primarily affect the functioning of the cell by stimulation or inhibition. Their action is initiated through the activation of G-proteins located within the cell cytoplasm, which initiate various chemical reactions (Box 3.2). G-proteins may open ion channels or stimulate phosphorylation of internal proteins, thus generating the signalling cascade. Many peptide hormones function as neurotransmitters in the brain. The monoamine hormones are derivatives of the amino acids tryptophan and tyrosine.

Box 3.2

Action of peptide hormones

• Binds to receptor on cell membrane

• Hormone–receptor complex

• Altered internal state

— For example, by opening ion channel in membrane

— For example, by affecting an enzyme such as tyrosine kinase which may phosphorylate (and activate) a protein

— For example, by activating a G-protein and causing calcium release

• Altered cell response

Gonadotrophic glycoproteins

This group includes TSH (thyroid stimulating hormone), FSH, LH and hCG, all of which are structurally similar. Their structure is a globular protein which is a heterodimer formed of two polypeptide chains, a common alpha subunit and a unique beta subunit. The beta subunit has unique carbohydrate side-chains that bestow stability and biological activity. hCG is produced by the placental tissue (the cytotrophoblasts produce the alpha subunit and the syncytiotrophoblast produces the beta subunit), whereas the other gonadotrophic glycoproteins are produced by the anterior pituitary gland.

Somatomammotrophic polypeptides

This group of hormones includes prolactin (PRL), human placental lactogen (hPL; also known as human placental somatomammotrophin) and growth hormone (GH); GH is also known as somatotrophin, which has marked effects on tissue growth including the breasts. Their structure is a single polypeptide chain. PRL and hPL are involved with lactation. GH has a role in puberty including breast development. Although PRL and GH are pituitary hormones, the placenta also produces them in addition to hPL. However, the activity of the placental hormones is often not exactly the same as that of the pituitary hormones. For instance, placental GH has a higher affinity for the PRL receptor than has pituitary GH. The somatomammotrophic polypeptide hormones affect growth including angiogenesis, functioning of the immune system and metabolism.

Cytokines

Cytokines are small polypeptide chains. There is a large number of cytokines including inhibin, activin, epidermal growth factors and AMH (see Chapters 5 and 13 and Box 3.3). Cytokines have a broad range of activity. They are usually made in a variety of cell types rather than in a specific gland. Cytokines act on many different cell types, often interacting with and modulating each other's responses. Several cytokines have similar and overlapping functions. They usually have paracrine activity and often modulate or mediate the actions of other types of hormone. Cytokines act by binding to their specific receptors on the cell membrane; typically, these receptors are also tyrosine kinase (enzymes that transfer a phosphate group to a tyrosine residue of protein which then regulates the activity of other enzymes).

Box 3.3

Anti-Müllerian hormone

A good example of the range of activity demonstrated by cytokines is AMH which has long been known for its role in promoting regression of the Müllerian ducts in the male embryo (see Chapter 5). The female embryo does not produce AMH, so the Müllerian ducts develop into female internal genitalia. AMH is secreted from the Sertoli cells of the testes and continues to be produced in male children but declines throughout adulthood. Women produce AMH, from the granulosa cells of the ovary, from puberty onwards; the role of AMH in the ovary is to limit excessive follicular recruitment by FSH, so it controls the number of primary follicles formed. It seems that puberty is preceded by a rise in AMH in girls and by a fall in AMH in boys. The changing levels of AMH also affect brain development via AMH receptors and are thought to mediate gender-specific behaviour. In women, AMH seems to be one of the best markers for ovarian reserve (the number of remaining follicles in the ovaries) and can be used to predict menopause and also the likely effectiveness of assisted reproductive technologies (Broekmans et al., 2008). Synthetic AMH is potentially a therapy for rapidly proliferating cancer cells and endometriosis as it inhibits not only growth and development of Müllerian ducts but also other tissues which express AMH receptors; as it has little known toxicity, it appears to be a suitable adjunct to other treatment and has an effect on some drug-resistant tumours (MacLaughlin and Donahoe, 2010).

Small peptide hormones

This group of hormones includes gonadotrophin (GnRH), a decapeptide (i.e. a chain of 10 amino acids) from the hypothalamus, and other releasing hormones, oxytocin, antidiuretic hormone (ADH; also known as vasopressin), β-endorphin (described in Chapter 13) and vasoactive intestinal peptide (VIP). Most of these small peptide hormones are initially produced in the form of pre-prohormones (large inactive polypeptide precursors). The pre-prohormone is then processed in the endoplasmic reticulum to form a prohormone. The processing may involve glycosylation (addition of polysaccharides) or removal of the N-terminal signal sequence. Prohormones often contain redundant amino acid residues that were required to direct the folding of the molecule into its active configuration but then have no further function. Endopeptidases cleave the prohormone, thereby producing the mature functional form of the hormone just before it is released from the cell. Some of the ‘pro’-fragments of the prohormones also exert a biological effect. The identification of secondary sites of hormone production, such as GnRH being produced in the placenta and ovary and oxytocin being produced in the testes and uterus, suggests that these small peptide hormones have diverse roles and may function as neurotransmitters (Johnson, 2007).

Monoamine hormones

This group includes catecholamines (dopamine, adrenaline and noradrenaline) and melatonin, all of which are derived from tyrosine (an amino acid) and may have a role in neuroendocrine control mechanisms. The medulla of the adrenal gland is a modified sympathetic ganglion; its cell bodies release adrenaline and noradrenaline (in the ratio 4:1) into the blood. Its effects, therefore, augment sympathetic nervous system activity. Dopamine is synthesized from tyrosine and then can be sequentially modified to form noradrenaline and then adrenaline. Dopamine released from the hypothalamus affects prolactin secretion (see Chapter 16). Melatonin, from the pineal gland, may have a role in seasonal and environmental influences on reproductive capability, which are particularly important in species other than humans.

Hormone transport

Peptide and protein hormones are water-soluble and are carried dissolved in the blood, whereas steroid hormones circulate bound to plasma proteins. When hormones are secreted into the blood supply, a large proportion become protein-bound, leaving only a small proportion free (unbound and able to access the target cell) and physiologically active. There are many types of hormone-binding proteins, all of which are colloidal in nature. Some hormones bind with great affinity to specific proteins. Other proteins may bind to numerous different hormones with different affinity rates that may be affected by the concentration of the hormone. Therefore, the amount of hormone present may affect its activity. For instance, oxytocin at high concentrations binds to ADH (or vasopressin) receptors within the renal tubule. During labour, levels of oxytocin do not normally rise until the end of the first stage. However, exogenous oxytocin can be administered to augment uterine contractions. If the administration of oxytocin is high and prolonged, however, water retention can occur because oxytocin also stimulates the ADH receptors. This overlap in the biological activity of hormones is described as promiscuity.

Hormonal regulation

One of the most important functions of the endocrine system is maintenance of the internal environment. This ‘steady’ state is described as homeostasis (see Chapter 1). Homeostatic mechanisms buffer changes within the external environmental conditions. For example, mammals have evolved to be homeothermic (warm-blooded) so that the chemical processes essential for physiological function proceed under optimal conditions of temperature. Fluctuations in temperature are monitored and the homeostatic mechanisms ensure that body temperature is held within narrowly defined limits. Homeostasis is achieved through the integration of the neural system with the endocrine system, commonly referred to as feedback systems.

As mentioned above, hormonal release is often instigated by neurological stimulation. Hormone release may also be stimulated by another hormone. Factors that facilitate the release of hormones are referred to as positive influences and factors that inhibit the release of hormones are termed negative influences. The negative feedback tends to slow down a process and maintain stability whereas positive feedback tends to speed up a process and generate rapid change.

Positive feedback describes a specialized chain of events involving one or more hormones in which there is a cycle of positive effects, greatly amplifying the original signal (Fig. 3.4). An example of positive feedback is the maintained production of PRL secretion from the anterior pituitary gland during lactation. Suckling of the infant stimulates PRL secretion, which maintains lactation. If suckling decreases or stops then the amount of stimulation decreases and PRL production is reduced. Other examples of positive feedback include coagulation of blood and the hormonal control of parturition.

Negative feedback describes a similar specialized chain of events involving one or more hormones, except that here there is a cycle of negative influence (Fig. 3.4). An example of negative feedback is that the anterior lobe of the pituitary gland produces TSH, which stimulates the thyroid gland to produce thyroid hormone. TSH production is, however, inhibited by the presence of thyroid hormone, the downstream production of the pathway.

Hormones may be released by the presence of a certain stimulus. For example, insulin release depends on plasma glucose levels. Many specific metabolic pathways are activated by the build-up of specific metabolites within the internal environment. Similarly, some hormones may be inhibited by the presence of a signal. This may be another hormone, such as adrenaline, neurological, such as light stimulation inhibiting melatonin release from the pineal gland, or chemical, such as insulin inhibiting the release of glucagon.

Hormone action

Hormones have their effects by interacting with a specific receptor. The receptor structure corresponds to the structure of the hormone (or ‘ligand’) so that the two fit together in a way which is often described as being a lock and a key. The interaction of the hormone and its receptor triggers the intercellular steps resulting in the consequences of the hormone action. The effects of hormones depend on a number of factors including affinity of the hormone for the receptor, agonist–antagonist effects, receptor number and hormone levels. Receptor number is important in the selection of the dominant follicle (see Chapter 4) and the increased sensitivity of the uterus to oxytocin in early labour (see Chapter 13). A lack of receptor expression can cause abnormal development, such as testicular feminization in the absence of androgen receptors (see Chapter 5). Genetic variations in the structure of receptors, for instance caused by single nucleotide polymorphisms, can influence the binding of the hormone to its receptor and affect an individual's sensitivity and responses to the hormone (Johnson, 2007). Hormone levels are affected by local circulation, stability, metabolism and excretion. Many hormones are inactivated within the blood, liver and their specific target cells. The breakdown of hormones is achieved by the action of various enzymes.

Hormone secretion may fluctuate with time. For instance, secretion of testosterone and prolactin exhibit circadian rhythms (characteristic pattern of changes during a 24-h period), whereas GnRH, FSH, LH and PRL are released in a pulsatile fashion. A continuous infusion of these hormones would diminish their response as the constant occupancy of the receptors uncouples them from the second-messenger system, effectively exhausting the cell. A high blood flow increases dissipation of hormones and is likely to increase a systemic endocrine response but decreases paracrine response.

Levels and metabolism of binding proteins will also affect the activity of hormones. The protein-bound hormone complex renders the bound hormone inactive but also protects the hormone from enzymatic degradation. Hormone turnover may be affected by multiple sites of production. Different tissues may have different feedback mechanisms controlling hormone production. Replicating hormone production occurs physiologically from the placental cells, but also pathologically from tumours. Hormones and their metabolites may be excreted via the kidney during the formation of urine. As the rate of excretion of many hormones is proportional to the rate of secretion, excretion rate indicates secretion rate. Generally, peptide hormones are readily metabolized by blood enzymes and are easily excreted, so their half-life in the blood is short compared with that of protein-bound steroid hormones.

Levels of hormones may change within the tissues themselves as hormones can be converted to a form with a higher biological activity. For instance, the enzyme 5α-reductase in many of the target tissues for testosterone converts testosterone to 5α-dihydrotestosterone, which has twice the biological activity. A deficiency of this enzyme can cause poor development of the male external genitalia (see Box 3.4). The target cell may metabolize a hormone. Peptide hormones are endocytosed and catabolized and the receptors are recycled.

Box 3.4

5α-Reductase deficiency

In the Dominican Republic, there is an increased incidence of an autosomal recessive condition resulting in 5α-reductase deficiency (Imperato-McGinley et al., 1986). 5α-Reductase is the enzyme that converts testosterone to the more biologically active 5α-dihydrotestosterone within the target cell. The lack of enzyme means that there is a diminished response to testosterone during fetal sexual development (see Chapter 5), so an affected baby may have small and ambiguous genitalia, appearing female at birth (testicular feminization). However, at puberty the surge in testosterone production is adequate to stimulate the cells; therefore, the child then develops male external genitalia. This condition is known as ‘Guevodoces’ (penis-at-twelve).

An agonist is a ligand or substance that binds to a receptor on the cell membrane or within the cytoplasm and activates a response. An antagonist also binds to the receptor often partially and does not therefore activate it, thus blocking or inhibiting the normal physiological response of the receptor. By occupying the receptor site, a competitive antagonist blocks the action of the specific hormone (agonist) that normally binds to the site; antagonists can also be non-competitive. A partial agonist activates a receptor to a lesser degree and elicits a smaller physiological response. The physiological overlap of oxytocin and ADH is an example of an agonist effect. The molecular structures of oxytocin and ADH are similar. Oxytocin can elicit the same biological response as ADH because it can bind to the same receptor sites. Therefore, oxytocin is agonistic to the ADH receptor and may be described as an ADH agonist. Progesterone acts as a glucocorticoid agonist and affects metabolism (see Chapter 11).

A number of natural and environmental chemicals can mimic the effects of hormones and act as antagonists or agonists. These are detailed in Box 3.5.

Box 3.5

Environmental influences on hormonal expression

A number of environmental chemicals, such as phthalates (plasticizers) and PCBs (polychlorinated biphenyls), exert hormone-like effects. The chemicals may mimic or antagonize endogenous hormones, disrupt synthesis and metabolism of endogenous hormones and/or affect receptor expression. These oestrogenic contaminants were initially linked to abnormal sexual development in wild animals and fish but effects on humans, such as reproductive abnormalities in male fetuses and effects on male fertility, are also under investigation. The pesticide DDT has been associated with reduced sperm counts and decreased libido. Chemicals used in plastics have been demonstrated to have oestrogenic properties. Degradation of alkylphenols used in detergents releases oestrogenic compounds. These environmental chemicals have been implicated in the increased incidence of testicular cancer, hypospadias (incomplete fusion of the urogenital folds of the penis), cryptorchidism (undescended testicles), breast cancer and endometriosis. It has also been suggested that fetal development, particularly of reproductive organs, may be affected by exposure to these compounds. The protective effect of phytoestrogens (see Chapter 4) may be related to interaction with environmental contaminants. Phytoestrogens, such as genestein from soy protein, may affect the length of the menstrual cycle and have similar protective effects on cardiovascular health and bone mineralization as endogenous oestrogen.

Endocrine glands, hormones and reproduction

Hormones can influence the ability of the target cell to respond by regulating the number of hormone receptors. Prolonged exposure to a low concentration of hormone may increase the number of receptors expressed by the cell (described as ‘up-regulation’). Conversely, prolonged exposure to a high concentration of hormone might decrease the number of receptors for that hormone (described as ‘down-regulation’). For instance, the expression of oxytocin receptors is down-regulated on prolonged exposure to oxytocin; this may explain the lack of response to exogenous oxytocin in induction of labour (see Chapter 13). Hormones can also affect receptors for other hormones, increasing or decreasing their effectiveness. When one hormone has to be present for another to have its full effect, it is described as permissive.

The endocrine glands and their main functions are summarized in Table 3.4.

The pituitary gland is a pea-sized gland at the base of the brain which is connected to the hypothalamus via the tuberoinfundibular pathway. It is often likened to a ‘master’ gland as it secretes hormones which regulate a broad range of body activities including trophic hormones which regulate other target endocrine glands. The pituitary gland has two main lobes, the anterior lobe (or adenohypophysis) and the posterior lobe (or neurohypophysis) (Fig. 3.5). The anterior lobe originates from the primitive oral cavity, whereas the posterior lobe is a projection of the hypothalamus. The anterior lobe produces hormones such as LH and FSH that regulate gametogenesis and steroidogenesis by the gonads (see Chapter 4). The maintenance of lactation is achieved through the production of PRL (see Chapter 16). The anterior lobe also produces PRL, TSH, GH, adrenocorticotrophic hormone (ACTH) and endorphins. The posterior lobe of the pituitary gland does not produce hormones but stores and secretes oxytocin and ADH, the latter being also known as vasopressin. The tiny intermediate lobe of the human pituitary gland, which is almost indistinguishable from the anterior pituitary, produces melanocyte-stimulating hormone (MSH).

The thyroid gland is butterfly-shaped and is the largest endocrine gland. It lies in front of the trachea, posterior to the larynx, and produces thyroid hormones. Thyroid hormones affect all tissues in the body and regulate metabolic rate, growth, brain development and function. The thyroid hormones, which contain iodide, are thyroxine (T₄) which is circulated and converted to the active form, and triiodothyronine (T₃) within the target tissues. Essentially T₄ is the prohormone and T₃ is 5–10 times more active than T₄. During pregnancy, the fetus initially utilizes maternally derived thyroxine, so the maternal thyroid gland hypertrophies (increases in size) to compensate for this. This is achieved by the thyrotrophic effect of hCG and a placentally derived hormone called human chorionic thyrotrophin. Thyroid hormones are essential for development and maturation of the fetal brain. Maternal thyroid gland activity is stimulated by oestrogens and hCG; the changes contribute to glucose provision for the fetus. The increase in thyroid activity increases the basal metabolic rate of the pregnant woman, resulting in an increase of maternal and fetal oxygen consumption. The parafollicular cells of the thyroid gland produce calcitonin, which is involved in the metabolism of calcium and phosphorus, in response to hypercalaemia. Calcitonin promotes the uptake of calcium by bone; levels increase in pregnancy and it is suggested that this may protect the maternal skeleton from excessive bone resorption. Hyperthyroidism is an overactive thyroid gland and hypothyroidism is an underactive thyroid gland; both conditions can affect fertility and treatment of either condition can be affected by pregnancy.

There are about four parathyroid glands, closely associated with the thyroid gland, that produce parathyroid hormone to maintain calcium homeostasis. Parathyroid hormone levels increase in response to a fall in serum calcium; it causes a decrease in urinary calcium excretion, increased mobilization of calcium from bone and, indirectly, causes an increase in calcium absorption (via an increase in vitamin D). Although parathyroid hormone is the primary regulator of 1,25-dihydroxyvitamin D synthesis in the non-pregnant state, it may not be particularly important in pregnancy as levels do not change much in pregnancy, and women without functioning parathyroid glands still have a raised level of circulating 1,25-dihydroxyvitamin D during pregnancy (Fig. 3.6).

The adrenal glands are triangle-shaped glands situated on top of the kidneys that regulate the response to stress by synthesizing corticosteroids (from the cortex of the gland) and catecholamines (from the medulla of the gland). Glucocorticoids, such as corticosterone and cortisol, are involved in the regulation of carbohydrate metabolism, the body's responses to stress and the regulation of the immune system. Carbohydrate metabolism is altered during pregnancy but it would appear that the fetal–maternal interaction concerning carbohydrate metabolism is mediated through the action of other hormones (see Chapter 11). Corticotrophin-releasing hormone (CRH) from the hypothalamus controls the release of ACTH from the anterior pituitary which regulates the production of hormones from the adrenal cortex; this is described as the hypothalamic–pituitary–adrenal axis. In pregnancy, maternal CRH levels increase dramatically, predominantly as a result of placental production. Placental CRH also enters the fetal circulation and may play a role in fetal organ maturation and also parturition. During pregnancy, ACTH levels double and cortisol levels increase. The adrenal glands also produce steroid hormones and mineralocorticoids such as aldosterone, which are principally involved in the regulation of the electrolyte balance of the body (see Chapter 2). Aldosterone levels increase in pregnancy as a response to increased renin and angiotensin II levels.

The gonads are responsible for the production of the sex steroids. In men, the testes predominantly produce testosterone. In women, the ovary produces oestrogens and progesterone. The endocrine cells of the gonads lack the enzymes to produce mineralocorticoids and glucocorticoids. The gonadal function of the regulation of reproduction is discussed in Chapter 4.

Fetal endocrinology

Many of the endocrine and metabolic changes of pregnancy are results of hormonal signals originating from fetal–placental unit (FPU), which is a major site of protein and steroid hormone production and secretion. The interactions of neuronal and hormonal factors mediated by the FPU are critical in directing the initiation and maintenance of pregnancy, maternal adaptations to pregnancy, fetal growth and development, coordination of the timing of parturition and preparation for lactation. Production of oestradiol involves cooperation between the maternal and fetoplacental systems (see Chapter 11). The fetal endocrine system is also involved in the differentiation and development of the sexes (see Chapter 5).

Key points

• The endocrine system and the nervous system interact and are involved in communication and maintenance of the internal environment.

• The classic description of a hormone as a substance released from a gland and transported in the blood to its target organ(s) cannot be applied to all hormones.

• Hormones can be classified structurally as monoamine, protein, peptide or lipid (steroid) hormones.

• Steroid hormones are produced from cholesterol precursors and include mineralocorticoids (such as aldosterone), glucocorticoids (such as cortisol) and sex steroids (oestrogen, progesterone and testosterone).

• Steroid hormones circulate bound to plasma proteins and exert their effect by altering protein synthesis in their target cells.

• Peptide hormones and catecholamines circulate in the plasma and affect signal transduction in their target cells.

• Hormonal effects are modulated by binding proteins, receptor expression, hormone metabolism and agonist–antagonist effects.

• Testosterone and oestrogen are responsible for the development and maintenance of sexual characteristics and fertility. Progesterone is involved in preparation for and maintenance of pregnancy.

Application to practice

During pregnancy, apart from the growth of the fetus, there is much tissue growth and development within the mother that is controlled by the action of hormonal changes within the maternal system and interactions with hormones produced by the fetal–placental complex.

Throughout the entire antenatal, perinatal and postnatal periods, the midwife should be able to observe these physiological changes and use them to form an assessment of the progression and well-being of the pregnant woman and fetus.

Gestational diabetes results from a reduced capacity to increase insulin production to compensate for the increase of glucose orchestrated by placental hormones and, in severe cases insulin therapy may be required to minimize the risks to the fetus, for example macrosomia. Women with type one diabetes may require significantly more insulin during pregnancy to compensate for the pregnancy induced hyperglycaemia.

Other endocrine disorders are also complicated by pregnancy, for example, hypothyroidism resulting in an increase in the amount of thyroxine required as the pregnancy progresses.

Annotated further reading

Holt, R.I.G.; Hanley, N.A., Essential endocrinology and diabetes. (2006) Wiley Blackwell, Oxford .

An excellent textbook which is supported by introductory chapter summaries, integrated case studies and clear diagrams.

Carlson, N.R., Physiology of behaviour. ed 9 (2009) Pearson Education, New York .

An interesting and comprehensive exploration of how physiological processes regulate and influence the behaviour and psychology of an organism; this textbook describes sexual behaviour in depth, relating it to endocrine and neurological interactions.

Greenstein, B.; Wood, D., Endocrinology at a glance. ed 2 (2006) Wiley Blackwell, Oxford .

Introduces the study of endocrinology in a clear, precise and easy-to-understand way.

Johnson, M.H., Essential reproduction. ed 6 (2007) Blackwell Science, Oxford .

An integrated and well-organized research-based textbook that explores comparative reproductive physiology of mammals, including anatomy, physiology, endocrinology, genetics and behavioural studies.

Finlayson, A.; Horton-Szar, D., Crash course: endocrine and reproductive systems. ed 3 (2007) Mosby, London .

This book provides essential information for students who need to have a basic understanding of the endocrine and reproductive systems.

References

Bhutta, M.F., Sex and the nose: human pheromonal responses, J R Soc Med 100 (2007) 268–274.

Broekmans, F.J.; Visser, J.A.; Laven, J.S.; et al., Anti-Mullerian hormone and ovarian dysfunction, Trends Endocrinol Metab 19 (2008) 340–347.

Brooker, C.G., Human structure and function. ed 2 (1998) Mosby, St Louis .

Gordon, I.; Zagoory-Sharon, O.; Leckman, J.F.; et al., Oxytocin and the Development of Parenting in Humans, Biol Psychiatry (2010).

Halpern, M.; Martinez-Marcos, A., Structure and function of the vomeronasal system: an update, Progress Neurobiol. 70 (2003) 245–318.

Iles, R.K.; Chard, T., Human chorionic gonadotrophin expression by bladder cancers: biology and clinical potential, J Urol 145 (1991) 453.

Imperato-McGinley, J.; Gautier, T.; Peterson, R.E.; et al., The prevalence of 5-alpha-reductase deficiency in children with ambiguous genitalia in the Dominican Republic, J Urol 136 (1986) 867–873.

Insel, T.R., Oxytocin—a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic and comparative studies, Psychoneuroendocrinology 17 (1992) 3–35.

Johnson, M.H., Essential reproduction. ed 6 (2007) Blackwell, Oxford .

MacLaughlin, D.T.; Donahoe, P.K., Mullerian inhibiting substance/anti-Mullerian hormone: a potential therapeutic agent for human ovarian and other cancers, Future Oncol 6 (2010) 391–405.