Neuroendocrinal mechanism of parturition

Neuroendocrinal mechanism of parturition

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My book reads,

"The fetus signals that it is mature by secreting certain hormones that diffuse across the placenta into mother's blood and cause the secretion of oxytocin from her posterior pituitary."

I would like to know what exactly are these hormones and their sites of production in the foetus, as well as their mode of action.

Also, I was wondering whether these hormones are released even during premature births? I doubt this because what I understand from the lines of my book is that it has to be a signal by the foetus that it is 'fully developed', whereas if it is not secreted it would not stimulate the secretion of oxytocin. This is creating a bit of confusion.

A detailed explanation would be a great help

Thank you

These hormones are progesterone and estrogens. They are actually secreted by the placenta, in increasing amounts as the fetus matures:

(Colorado State, R. Bowen)

You can see that the placenta produces both types of hormone in increasing amounts until birth. Additionally, the hormone relaxin is secreted by the placenta and thought to aid in parturation:

Relaxin is a hormone thought to act synergistically with progesterone to maintain pregnancy. It also causes relaxation of pelvic ligaments at the end of gestation and may therefore aid in parturation. In some of the species in which relaxin is known to be produced, it is produced by the placenta, while in others, the major source is the corpus luteum. In some species, relaxin is produced by both the corpus luteum and placenta. - R. Bowen

Neuroendocrine mechanisms in pregnancy and parturition

The complex mechanisms controlling human parturition involves mother, fetus, and placenta, and stress is a key element activating a series of physiological adaptive responses. Preterm birth is a clinical syndrome that shares several characteristics with term birth. A major role for the neuroendocrine mechanisms has been proposed, and placenta/membranes are sources for neurohormones and peptides. Oxytocin (OT) is the neurohormone whose major target is uterine contractility and placenta represents a novel source that contributes to the mechanisms of parturition. The CRH/urocortin (Ucn) family is another important neuroendocrine pathway involved in term and preterm birth. The CRH/Ucn family consists of four ligands: CRH, Ucn, Ucn2, and Ucn3. These peptides have a pleyotropic function and are expressed by human placenta and fetal membranes. Uterine contractility, blood vessel tone, and immune function are influenced by CRH/Ucns during pregnancy and undergo major changes at parturition. Among the others, neurohormones, relaxin, parathyroid hormone-related protein, opioids, neurosteroids, and monoamines are expressed and secreted from placental tissues at parturition. Preterm birth is the consequence of a premature and sustained activation of endocrine and immune responses. A preterm birth evidence for a premature activation of OT secretion as well as increased maternal plasma CRH levels suggests a pathogenic role of these neurohormones. A decrease of maternal serum CRH-binding protein is a concurrent event. At midgestation, placental hypersecretion of CRH or Ucn has been proposed as a predictive marker of subsequent preterm delivery. While placenta represents the major source for CRH, fetus abundantly secretes Ucn and adrenal dehydroepiandrosterone in women with preterm birth. The relevant role of neuroendocrine mechanisms in preterm birth is sustained by basic and clinic implications.

Composition and properties of milk

Milk can be regarded as an emulsion of fat globules in a colloidal solution of protein together with other substances in true solution. Two constituents of milk—the protein casein and milk sugar, or lactose—are not found elsewhere in the body.

Breastfeeding is particularly advantageous because of the nutritional, immunologic, and psychological benefits. Human breast milk is superior to modified cow’s milk formulas, which may lack essential and beneficial components and are not absorbed as easily or as quickly by the infant. Maternal breast milk provides vitamins, minerals, protein, and anti-infectious factors antibodies that protect the infant’s gastrointestinal tract are supplied, resulting in a lower rate of enteric infection in breast-fed than in bottle-fed babies. The bonding that is established through breast-feeding is advantageous to building the parent-child relationship.

The nutritional status of the mother is important throughout this period. The mother’s daily caloric intake must increase significantly in order to replenish the mother’s nutrient and energy stores. The use of drugs or smoking by the mother can adversely affect the infant many drugs are secreted in breast milk, and smoking reduces breast milk volume and decreases infant growth rates.

The milk released from the breast when lactation starts differs in composition from the mature milk produced when lactation is well established. The early milk, or colostrum, is rich in essential amino acids, the protein building blocks essential for growth it also contains the proteins that convey immunity to some infections from mother to young, although not in such quantity as among domestic animals. The human infant gains this type of immunity largely within the uterus by the transfer of these antibody proteins through the placenta the young baby seldom falls victim to mumps, measles, diphtheria, or scarlet fever. For a short time after birth, proteins can be absorbed from the intestine without digestion, so that the acquisition of further immunity is facilitated. The growth of harmful viruses and bacteria in the intestines is probably inhibited by immune factors in human milk. After childbirth the composition of milk gradually changes within four or five days the colostrum has become transitional milk, and mature milk is secreted some 14 days after delivery.

Some variations between human colostrum, transitional milk, and mature milk and cow’s milk are shown in Table 2. The greater amount of protein in unmodified cow’s milk is largely responsible for its dense, hard curd, which the infant cannot digest the difficulty can be avoided by heat treatment or dilution of the milk. Ordinarily, when cow’s milk is fed to young infants, it is modified so as to match its composition as far as possible to breast milk.

Some constituents of human colostrum, transitional, and mature milk and of cow's milk
(average values per 100 millilitres whole milk)
colostrum (1–5 days) transitional (6–14 days) mature (after 14 days) cow's milk
*Kilocalorie sufficient energy to raise the temperature of 1 kilogram of water 1 degree Centigrade.
energy, kcal* 58 74 71 69
total solids, g 12.8 13.6 12.4 12.7
fat, g 2.9 3.6 3.8 3.7
lactose, g 5.3 6.6 7.0 4.8
protein, g 2.7 1.6 1.2 3.3
casein, g 1.2 0.7 0.4 2.8
ash, g 0.33 0.24 0.21 0.72
calcium, mg 31 34 33 125
magnesium, mg 4 4 4 12
potassium, mg 74 64 55 138
sodium, mg 48 29 15 58
iron, mg 0.09 0.04 0.15 0.10

PNECs as sensory transducers

In the mid-20th century, the nature of intrapulmonary chemoreceptors was yet to be determined, even though physiological observation anticipated their existence (Dawes and Comroe, 1954) and indicated that hypoxia evokes pulmonary vasoconstriction, possibly via the monoamine neurotransmitter serotonin (5-HT) (Duke, 1951 Sjoerdsma, 1959). Moreover, a series of morphological observations by Lauweryns and Cokelaere (1973) identified structural similarities between NEBs and chemoreceptors in other tissues, such as taste buds and carotid bodies. Furthermore, PNECs express and secrete 5-HT in response to hypoxia (Lauweryns and Cokelaere, 1973 Lauweryns et al., 1977). Recent research further showed that PNECs can respond not only to hypoxia but also to several environmental stimuli and mechanical forces (Cutz et al., 2013). Here, we describe the physiological significance of PNECs as a sensory component of the lung.

Oxygen sensing

Pulmonary tissue senses O2 in the inhaled air to control breathing rate via the central nervous system (Dawes and Comroe, 1954) this homeostatic response equilibrates O2 availability in different environments. For instance, when humans get a workout at high altitude, where air pressure is relatively low, their ventilation frequency increases to uptake more O2 into the lungs (West et al., 1983). In 1993, Youngson et al. reported that PNECs in NEBs express an O2-sensing complex consisting of an NADPH oxidase coupled to an O2-sensitive K + channel in the plasma membrane (Youngson et al., 1993). They showed that the K + channels on PNECs close down in hypoxic conditions, while voltage-sensitive Ca 2+ channels open up to facilitate the influx of extracellular Ca 2+ , leading to Ca 2+ -dependent exocytosis of DCVs (Cutz et al., 2013). Release of DCV cargo affects the physiological functions of lung tissues through direct or indirect interaction via vagal afferent and central nerves (Youngson et al., 1993 Wang et al., 1996 Cutz and Jackson, 1985) (Fig. 1).

Hypoxia triggers 5-HT release from NEBs, which occurs within the physiological range expected in the airway [oxygen partial pressure (PO2), ∼95 mmHg] (Fu et al., 2002). 5-HT induces vasoconstriction of large and small muscular pulmonary arteries (MacLean et al., 1996 Morecroft et al., 1999). Thus, PNECs link hypoxia and the serotonergic system to modulate pulmonary homeostasis. By contrast, CGRP is a potent vasodilator (Brain et al., 1985). Although CGRP is persistently secreted during normoxia to maintain vascular smooth muscle contraction, hypoxia depletes CGRP from NEBs, eventually reducing the pressor response of pulmonary vasculature (Tjen et al., 1998). In summary, PNECs may coordinate blood flow in the lung by regulating the secretion of these reciprocally bioactive peptides.

The peculiar positioning of NEBs at airway bifurcation points seems to relate to the structural benefits of rapid sensing of O2-level changes. The larger NEBs located next to the proximal branching points of the proximal airway respond to hypoxia quicker than the carotid body, which senses alterations in O2 levels in the blood. In future studies, analyzing genetically modified mice with altered NEB distribution could unveil the physiological significance of NEBs for O2 sensing in detail.

Nicotine sensing

PNEC hyperplasia has been reported in smoking-associated lung disorders, including chronic obstructive pulmonary disease (COPD) and asthma. Nicotine inhalation via cigarette and e-cigarette smoking promotes pulmonary edema and lung damage, along with abnormal leukocyte increases, leading to adverse effects in the lungs and the entire body (Ahmad et al., 2019). Nicotine is an agonist for nicotinic acetylcholine receptors (nAChRs), which physiologically respond to the neurotransmitter acetylcholine. Prenatal nicotine exposure increases NEB abundance in primate models (Fu and Spindel, 2009). How do PNECs sense nicotine exposure? Does nicotine-triggered functional alteration of PNECs link to pulmonary diseases?

PNECs express functional nAChRs similarly to hypoxia, nicotine exposure suppresses the O2-sensitive A-type K + channel, evoking an excitatory inward current (Sartelet et al., 2008 Fu et al., 2007). The excited NEBs secrete 5-HT through the a7-nAChR pathway (Schuller et al., 2003). These findings imply that nicotine induces pulmonary hypertension, potentially via enhanced 5-HT secretion from hyperplastic PNECs. Moreover, intravenous nicotine injections evoke reflex apnea in the expiratory position in cats and dogs, resembling the P2RY1 reflex (Domaye, 1955 Takasaki, 1956). The involvement of NEB–P2RY1 + neuron communication in nicotine-induced chemoreflexes is an attractive topic for future research. Nicotine-induced a7-nAChR signaling cascades regulate cancer-associated features, including cell proliferation (Hajiasgharzadeh et al., 2019). Thus, their activation could lead to the aberrant PNEC hyperplasia found in smoking-associated lung diseases. Because 97% of small-cell lung cancer (SCLC) patients have a history of smoking (Pesch et al., 2012), nAChR signaling in SCLC development could be another relevant research topic.


Ventilation dynamics generate mechanical forces in the lung epithelium. Computational simulations have demonstrated that branching points – where nodal NEBs locate – are subjected to a higher air pressure than the surrounding epithelium (Sul et al., 2014). Fetal breathing – respiratory-like rhythmic activity – produces amniotic fluid flows into and out of the lung (Plosa and Guttentag, 2018). These amniotic fluid waves could also intermittently hit the branching points during development. Thus, fetal and post-natal breathing may mechanically stimulate nodal NEBs in every respiratory cycle.

Several studies have shown that mechanosensing is a PNEC function. Piezo2 and Trpc5 (Box 1) are expressed on PNECs and likely play key roles in mechanosensing. In addition, PNECs are innervated by Piezo2 + afferent fibers responsible for the Hering–Breuer mechanoreflex (Box 1) (Lembrechts et al., 2012 Nonomura et al., 2017). Cultured NEBs induce a selective, fast, reversible and reproducible Ca 2+ rise in response to mechanical hypoosmotic stimuli (Lembrechts et al., 2012). Furthermore, mechanical stretch enhances 5-HT release from NEBs in rabbit models, further suggesting that PNECs might be mechanosensitive and are possibly capable of transducing mechanical information into neurotransmission (Pan et al., 2006). Another candidate mediator for PNEC mechanotransduction could be adenosine triphosphate (ATP), as known in various tissues (Kringelbach et al., 2015 Guan et al., 2018). In an ex vivo lung slice model, depolarization of PNECs with high K + releases the ATP stored in DCVs (De Proost et al., 2009).

Interestingly, P2X3 + nerves are exclusively associated with ATP + DCV-containing PNECs, which express the heteromeric purinergic P2X2/3 receptors (Brouns et al., 2000 Fu et al., 2004). PNEC-secreted ATP may bind to autoreceptors on PNECs, promoting its own secretion through an autocrine positive feedback loop.

Despite the above, the physiological significance of PNEC mechanosensing remains enigmatic. PNEC mechanotransduction might pace the diaphragmatic vertical movements through periodic neuronal activation to support smooth breathing. Moreover, the oversecretion of biological substances in response to artificial mechanical strain could contribute to ventilator-induced pediatric lung disease (see ‘PNECs in lung pathogenesis’ section).

Signaling center in asthmatic response

Asthma is the most frequently diagnosed chronic disorder among children and adults, affecting 339 million people worldwide, and the number of patients is increasing every year ( Asthma is a chronic disease of the innate and adaptive immune systems responding to allergens (Suarez et al., 2008 Pivniouk et al., 2020). Histologically, PNEC hyperplasia has been observed in asthmatic patients' lungs (Adriaensen and Timmermans, 2004 Sui et al., 2018). In addition, allergen challenges increase PNECs in animal models (Bousbaa and Fleury-Feith, 1991). Previous studies have implicated the immune-regulatory role of PNECs, and recent in vivo findings support this hypothesis.

Notably, Sui et al. (2018) demonstrated that endodermal Ascl1 (Box 1)-knockout mice, which are PNEC deficient, lack the allergen-induced asthmatic response. Furthermore, intratracheal administration of CGRP and gamma aminobutyric acid (GABA) to these mutants recovers the immune response, including goblet cell (Box 1) hyperplasia. The CGRP produced by PNECs stimulates type 2 innate lymphoid cells, enriched at airway branching points, which triggers immune responses to allergens. PNECs secrete GABA, which promotes goblet cell differentiation (Sui et al., 2018). Furthermore, Branchfield et al. (2016) described an increase in neuropeptide secretion in Robo1/2 mutant mice, in which PNECs fail to cluster, increasing immune responses and airway inflammation. Thus, PNEC clustering may act as a rheostat for the intrapulmonary immune system. These findings raise new questions concerning the detailed mechanisms by which allergens activate PNECs.

Inhaled glucocorticoids are widely used to suppress bronchial inflammation (Tripathi, 2016) and monoclonal antibodies to target type 2 asthma are currently emerging (Edris et al., 2019). Elucidating the links between PNECs and the type 2 immune responses could confirm that repurposing CGRP-targeted drugs is beneficial in inhibiting the asthmatic immune reaction. PNEC functions might be linked to Th-2 immune responses therefore, CGRP-targeting drugs could be considered for inhibition of inflammation in asthma.


In general, endocrine disruptors are thought to affect an organism’s endocrine system. Additionally endocrine disruptors are known to affect other diseases such as cancer and obesity ( Fig. 2 ).16� In the case of obesity, endocrine disruptors are called obesogens. This chapter deals with molecular mechanisms of endocrine disruptors already studied.

Common molecular mechanisms of endocrine disruptors. (A) Endocrine disruptors act as receptors (especially endocrine receptor) binding inhibitors. Most harmful effects are initiated by this inhibition and is shown by most endocrine disruptors mechanism. (B) When the targets of endocrine disruptors were adipocyte, endocrine disruptors can be obesogens. In this case, peroxisome proliferator activated receptor (PPAR) on mesenchymal cells or progenitor cells are the targets. (C) In the case of cancer, endocrine disruptors act on the cell cycle. Cyclin protein and p21 protein were known to regulate cancer cells when exposed to endocrine disruptors. ER, estrogen receptor MSC, mesenchymal stem cell. Cited from the article of Celik et al. (Chem Res Toxicol 200821:2195�), Masuno et al. (Toxicol Sci 200584:319�), and Ohtsubo et al. (Mol Cell Biol 199515:2612�).16�

1. Inhibition of endocrine receptors

Endocrine disruptors can affect every level of the endocrine system. First, they can disrupt the action of enzymes involved in steroidogenesis. These enzymes can be inhibited, as can the enzymes involved in metabolism of estrogens. For instance, some polychlorinated biphenyl (PCB) metabolites inhibit sulfotransferase, resulting in an increase of circulating estradiol.19 The transport of hormones is also targeted by certain compounds capable of interacting with the binding sites of sex hormone binding globulin, thus competing with endogenous estrogens.20 The most studied mode of action of endocrine disruptors is their ability to bind and activate endocrine receptors (ERs) in target tissue.16 However, it is of note that the two ERs mediate distinct biological effects in many tissues, such as the mammary glands, bone, brain, and vascular system in both males and females. Therefore, because ERα and ERβ show different tissue distribution and distinct physiological functions, endocrine disruptors could display agonist or antagonist activity in a tissue-selective manner or during development. Considering the significant differences in structural features and relative ligand binding affinity of the ER subtypes, endocrine disruptors can induce distinct conformational changes in the tertiary structure of the ERs, affecting the recruitment of cofactors differently. These interactions between ERs and coactivators/corepressors are critical steps in ER-mediated transcriptional regulation and consequently the modulation of the expression of ER-target genes.

Moreover, the genistein effect is often tissue specific, depending on numerous factors such as the expression of specific cofactors, the ERα/ERβ ratio, and the level of expression of certain intracellular kinases, including cytoplasmic tyrosine kinases. Genistein has been reported to have both proliferative and anti-proliferative effects in cancer cells.21 Endocrine disruptors generally act in 100 to 1,000 folds greater concentrations than estradiol but can have additive or synergic effects with endogenous estradiol or when they are present in combination.22 Furthermore, the ability of some endocrine disruptors to act as agonists in certain tissues and as antagonists in the others leads to the development and use of selective ER modulators, in particular for anti-hormonal treatments, such as tamoxifen and raloxifene. Some endocrine disruptors can also affect the ER non-genomic pathways and induce an endocrine disruption.23 For instance, a study performed on structurally different endocrine disruptors showed that at high concentrations, BPA and diethylstilbestrol are able to activate ERs via the activation of mitogen-activated protein kinase and phosphotidyl inositol 3-kinase in breast cancer cells. In addition, the activation of protein kinase C (PKC) by some endocrine disruptors has been observed.24 Interestingly, PKC has been reported to modulate ERα transcriptional activity.25 Therefore, synergic or additive effects between these pathways to combine the activation of ER signaling could be possible.

Cadmium is well known as a endocrine disruptor which affects the synthesis and/or regulation of several hormones.26,27 Indeed, cadmium affected progesterone synthesis in JC-410 porcine granulose cells and activated the ERα and/or mimic estrogen in different tissues (e.g., uterus and mammary gland) and breast cancer cell lines.28� Cadmium regulates androgen receptor gene expression and activity in LNCap cells, a hormone-dependent human prostate cancer cell line, and also mimics androgenic effects in rats and mice.31 In male rodents, it is well established that cadmium significantly alters the circulating levels of several hormones (e.g., testosterone, luteinizing hormone [LH], and follicle-stimulating hormone [FSH]).32 Moreover it decreased steroidogenic acute regulatory protein, LH receptor and cyclic adenosine monophosphate (cAMP) levels in the testis.33 Cadmium affected the circadian pattern release of noradrenaline, a regulator of hypothalamus hormone secretion, which resulted in changes in the daily pattern of plasma testosterone and LH levels.32 In addition, plasma levels of pituitary hormones (e.g., LH, FSH, prolactin, and adrenocorticotropic hormone) were modified after cadmium exposure.34

2. Obesity mechanism

Endocrine disruptors play another role in obesity and the metabolic programming of obesity risk. Their action predicts the existence of chemical obesogen, molecules that inappropriately regulate lipid metabolism and adipogenesis to promote obesity. Although until now, data have been scant some epidemiological and in vitro studies suggested a link between environmental chemical exposure and obesity.35

The endocrine disruptors inducing obesity are called obesogens and have been reviewed.35 Obesogens have been shown to target transcription regulators found in gene networks that function to control intracellular lipid homeostasis as well as proliferation and differentiation of adipocytes. The major group of regulators that is targeted is a group of nuclear hormone receptors known as peroxisome proliferator activated receptors (PPARα, δ, and γ). These hormone receptors sense a variety of metabolic ligands, including lipophilic hormones, dietary fatty acids, and their metabolites, and, depending on the levels of these ligands, control transcription of genes involved in balancing the changes in lipid balance in the body.36 In order to become active and properly function as both metabolic sensors and transcription regulators, the PPAR receptors must heterodimerize with another receptor known as the 9-cis retinoic acid receptor (RXR). The RXR receptor, itself, is the second major target of obesogens next to the PPAR receptors.35 The central regulator in this process is the PPARγ, which associates with the RXR receptors and binds DNA targets as a heterodimer to directly regulate the expression at the transcriptional level.37 PPARγ is considered to be the master regulator of adipogenesis and plays key roles in nearly all aspects of adipocyte biology.38 It was recently proposed that PPARγ may function in adipogenesis without the need to be activated by a ligand. When the ligand binding domain of PPARγ was mutated such that the receptor was unresponsive to known agonists, the ability of preadipocytes to differentiate into adipocytes in cell culture was unaffected.39 The most reasonable interpretation of these data is that either PPARγ can act as an unliganded transcription factor to mediate adipogenesis, or that an as yet unknown endogenous ligand is being produced in response to the induction cocktail. Several endocrine disruptors are known to affect PPARγ activity and induce adipogenesis.

Notable among these are organotins such as tributyltin and triphenyltin and certain phthalates.40,41 Triorganotins and phthalates also have the ability to induce adipocyte differentiation in a variety of cell culture models.42,43 Other endocrine disruptors are known to promote adipogenesis, but probably do not act through PPARγ. These include BPA, organophosphate pesticides, monosodium glutamate, and PBDEs.44,45 PCBs bind the aryl hydrocarbon receptor in adipocytes and increase adipogenesis.46 BPA and alkylphenols stimulate adipogenesis in 3T3-L1 cells, and BPA diglycidyl ether was recently shown to induce adipogenesis in human and mouse bone marrow-derived mesenchymal stem cells.17 Although several endocrine disruptors are associated with adipogenesis and obesity in animal models, tributyltin is the only endocrine disruptor known to cause in utero effects on adipocytes via activation of PPARγ.47 Prenatal exposure to tributyltin in mice led to a substantial increase in the amount of triglycerides in newborn tissues which normally have little to no fat at all, although, the experiments did not distinguish whether more lipid was stored in existing cells, more cells were produced, or both.43 Other endocrine disruptors are likely to promote adipogenesis, in utero, although it is possible that this is secondary to broader metabolic imbalances. For instance, certain PCBs and PBDEs reduce thyroid function as does the antibacterial compound triclosan.48,49 The mechanisms of action are not completely certain, but possible modes include interference with thyroid hormone synthesis, transport, metabolism, or clearance.50

3. Cancer mechanisms

Various studies have explored the role of endocrine disruptors in cancer. Breast cancer and prostate cancer are typical cancers caused by endocrine disruptors and compelling reasons to study endocrine disruptors.50 Despite various studies that have been completed, the direct roles of endocrine disruptors in cancer have not been clearly understood. Many researchers inferred that physiological unbalance created by endocrine disruptors might cause cancer. Generally endocrine disruptors are more harmful to woman than man and endometrial cancer and ovarian cancer are being researched.51

Epidemiologic data on the effects of endocrine disruptors on endometrial cancer are limited. Researchers found no association between endometrial cancer and 27 PCB congeners, 4 dichloro-diphenyl-trichloroethane-related compounds, and 13 other organochlorine compounds.52 Several retrospective occupational cohort studies also observed no association.53 In the Seveso industrial accident, tetrachlorodibenzodioxin exposure appeared to reduce the risk of uterine cancer, but the number of cases was too small for a comprehensive evaluation.54

There is some evidence that dietary isoflavones protect endometrial proliferation. Controversially, a randomized double-blind, placebo-controlled study on 298 post-menopusal women showed an increased incidence of endometrial hyperplasia following 5 years of treatment with 50 mg of soy isoflavones.55 Thus, phytoestrogenic supplements should be reconsidered, particularly in women at high risk for endometrial cancer. Isoflavones are known as beneficial materials but they can be harmful to the body because these are actually endocrine disruptors.

Ovarian function is controlled by the hypothalamus, pituitary, and auto-paracrine factors. Hormone-mimicking compounds can bind to cell receptors, interfere with hormone action, and affect ovarian function. It is not clear how endocrine disruptors affect ovarian function, but a disruption in gonadotropin (i.e., FSH and LH) secretion and feedback mechanisms involving estradiol (E2) and progesterone (P4) may be involved.

Alternatively, endocrine disruptors may affect ovarian hormone production and oocyte maturation. Damaged oocytes can affect overall hormone production and follicular function, resulting in an endocrinological imbalance (i.e., a decrease in E2 and P4, but an increase in FSH and LH) and ovarian failure. Ovarian cancer is the most prevalent type of gynecological cancer affecting women residing in Western countries. As more than 60% of tumors are diagnosed at stage III and certain forms of cancer are very aggressive, ovarian cancers are associated with a high mortality. While most cells undergo neoplastic transformation, including germ cells, granulose, and stromal cells, approximately 90% of tumors are derived from the ovarian surface epithelium. Similar to breast cancer, hormonal factors such as estrogen and xenoestrogens have been linked to ovarian cancer.56 However, the role of environmental toxins in ovarian cancer requires further study.

Neuroendocrinal mechanism of parturition - Biology


Human beings consist of many trillions of cells that must work together to sustain life. Fuel resources must be conserved or used appropriately, such as during responses to stressful situations. In addition, organs must be able to communicate with the brain to cause a change in behavior and physiology to maintain homeostasis. Hormones, as the messengers in the endocrine system, play an essential role in this communication. For example, the pancreas produces both insulin and glucagon. Insulin favors the transport of glucose into organs as well as the storage of excess glucose when blood glucose concentrations are high. Conversely, glucagon triggers the release of sugar stores and raises blood glucose concentration. Working together, these hormones ensure that there is enough glucose available for organ function, but that glucose levels are not so high as to cause damage to organ systems.

This is no inconsequential fact. Diabetes mellitus is one of the most common diagnoses in the United States and a major cause of morbidity and mortality. Type 1 diabetes mellitus is an autoimmune disease in which insulin-producing cells in the islets of Langerhans are destroyed type 2 diabetes mellitus is caused by end-organ insensitivity to insulin. In both cases, blood glucose concentrations rise to dangerous levels (sometimes up to ten times the normal concentration) and can cause significant damage to multiple organs, including the retina of the eye, the glomeruli of the kidneys, the coronary vessels of the heart and cerebral vessels of the brain, and nerves in the extremities. Left untreated (or, to be frank, even if treated in many cases), diabetes can lead to blindness, kidney failure, heart attacks, strokes, and amputation. Regardless of the field you enter, you will spend a significant amount of time working with diabetic patients and will have to think about the effects of this diagnosis on other diagnoses and their treatment.

In this chapter, we will explore the different types of hormones and how they work. We’ll survey the various endocrine organs and discuss the hormones each one produces. This is an extremely high-yield chapter: the MCAT frequently tests not only the content of the endocrine system (the hormones and their functions), but also the reasoning of the endocrine system (feedback loops and their regulation). Return to this chapter frequently during studying a thorough knowledge of this system will assuredly pay off in points on Test Day.

5.1 Mechanisms of Hormone Action

The endocrine system consists of organs, known as glands, that secrete hormones. Hormones are signaling molecules that are secreted directly into the bloodstream to travel to a distant target tissue. At that tissue, hormones bind to receptors, inducing a change in gene expression or cellular functioning. Not all hormones share the same structure and function. In order to understand how each hormone functions, it is first important to understand basic hormone structure.


Hormones can be subdivided into categories based on different criteria. First, hormones can be classified by their chemical identities. Hormones can be peptides, steroids, or amino acid derivatives.

Peptide Hormones

Peptide hormones are made up of amino acids, ranging in size from quite small (such as ADH) to relative large (such as insulin). Peptide hormones are all derived from larger precursor polypeptides that are cleaved during posttranslational modification. These smaller units are transported to the Golgi apparatus for further modifications that activate the hormone and direct it to the correct location in the cell. Such hormones are released by exocytosis after being packaged into vesicles.

Because peptide hormones are charged and cannot pass through the plasma membrane, these hormones must bind to an extracellular receptor. The peptide hormone is considered the first messenger it binds to the receptor and triggers the transmission of a second signal, known as thesecond messenger. There are many different receptor subtypes, and the type of receptor determines what happens once the hormone has stimulated the receptor.

The connection between the hormone at the surface and the effect brought about by second messengers within the cell is known as a signaling cascade. At each step, there is the possibility of amplification. For example, one hormone molecule may bind to multiple receptors before it is degraded. Also, each receptor may activate multiple enzymes, each of which will trigger the production of large quantities of second messengers. Thus, each step can result in an increase in the intensity of the signal. Some common second messengers are cyclic adenosine monophosphate (cAMP), inositol triphosphate (IP3), and calcium. The activation of a G protein-coupled receptor is shown in Figure 5.1. In this system, the binding of a peptide hormone triggers the receptor to either activate or inhibit an enzyme called adenylate cyclase, raising or lowering the levels of cAMP accordingly. cAMP can bind to intracellular targets, such as protein kinase A, which phosphorylates transcription factors like cAMP response element-binding protein (CREB) to exert the hormone’s ultimate effect. Keep in mind that protein kinase A can modify other enzymes as well as transcription factors, thus it can have a rapid or slow effect on the cell.

Figure 5.1. Mechanism of Action of a Peptide Hormone Peptide hormones bind to membrane-bound receptors to intiate a signal cascade, using second messengers like cAMP.

The effects of peptide hormones are usually rapid but short-lived because these hormones act through transient second messenger systems. It is quicker to turn them on and off, compared with steroid hormones, but their effects do not last without relatively constant stimulation.

Because peptides are generally water-soluble, peptide hormones can travel freely in the bloodstream and usually do not require carriers. This is in stark contrast to steroid hormones, as we will explore in the next section.

Steroid Hormones

Steroid hormones are derived from cholesterol and are produced primarily by the gonads and adrenal cortex. Because steroid hormones are derived from nonpolar molecules, they can easily cross the cell membrane. In fact, their receptors are usually intracellular (in the cytosol) or intranuclear (in the nucleus). Upon binding to the receptor, steroid hormone–receptor complexes undergo conformational changes. The receptor can then bind directly to DNA, resulting in either increased or decreased transcription of particular genes, depending on the identity of the hormone, as shown in Figure 5.2. One common form of conformational change is dimerization, or pairing of two receptor–hormone complexes. The effects of steroid hormones are slower but longer-lived than peptide hormones because steroid hormones cause alterations in the amount of mRNA and protein present in a cell.

Figure 5.2. Mechanism of Action of a Steroid Hormone Estrogen, like all steroid hormones, influences cell behavior by modifying transcription.


Peptide hormones have surface receptors and act via second messenger systems. Steroid hormones bind to intracellular receptors and function by binding to DNA to alter gene transcription.

Insulin is a peptide hormone, and it has to be released at every meal in order to be active. Thus, it has fast onset but is short-acting (as most peptide hormones are). Estrogen and testosterone are steroid hormones that promote sexual maturation. This is a slower, but longer-lasting change (as is true for most steroid hormones).

Steroid hormones are not water-soluble and, thus, must be carried by proteins in the bloodstream to be able to travel around the body. Some of these proteins are very specific, and carry only one hormone (such as sex hormone-binding globulin), while other proteins are nonspecific (such asalbumin). Note that hormones are generally inactive while attached to a carrier protein and must dissociate from the carrier to function. Levels of carrier proteins can change the levels of active hormone. For example, some conditions increase the quantity of the protein that carries thyroid hormones, thyroxine-binding globulin (TBG). This causes the body to perceive a lower level of thyroid hormone because the increased quantity of TBG binds a larger proportion of the hormone, meaning there is less free hormone available.

During pregnancy, high levels of estrogen and progesterone cause increased production of TBG, thyroxine-binding globulin. In order to compensate, pregnant women secrete much higher levels of the thyroid hormones. Thus, in order to diagnose thyroid disease in a pregnant woman, different reference values must be used.

Amino Acid-Derivative Hormones

Finally, amino acid-derivative hormones are less common than peptide and steroid hormones, but include some of the most important hormones discussed in this chapter, including epinephrine, norepinephrine, triiodothyronine, and thyroxine. These hormones are derived from one or two amino acids, usually with a few additional modifications. For example, thyroid hormones are made from tyrosine with the addition of several iodine atoms.

This chemistry of this family of hormones is considerably less predictable and is one of the few instances where overt memorization may be the best strategy. The catecholamines (epinephrine and norepinephrine) bind to G protein-coupled receptors while the thyroid hormones bind intracellularly.


The mechanism of action of the amino acid-derivative hormones should be memorized because it is so unpredictable. Epinephrine and norepinephrine have extremely fast onset but are short-lived, like peptide hormones&mdashthink of an adrenaline rush. Thyroxine and triiodothyronine, on the other hand, have slower onset but a longer duration, like steroid hormones&mdashthey regulate metabolic rate over a long period of time.


Some hormones, known as direct hormones, are secreted and then act directly on a target tissue. For example, insulin released by the pancreas causes increased uptake of glucose by muscles. Other hormones, known as tropic hormones, require an intermediary to act. For example, as discussed in Chapter 2 of MCAT Biology Review, gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH then acts on the gonads to stimulate testosterone production in the male and estrogen production in the female. GnRH and LH do not cause direct changes in the physiology of muscle, bone, and hair follicles rather, they stimulate the production of another hormone by another endocrine gland that acts on these target tissues. Tropic hormones usually originate in the brain and anterior pituitary gland, as these structures are involved in coordination of multiple processes within the body.

Most peptide and amino acid-derivative hormones have names that end in –in or –ine (insulin, vasopressin, thyroxine, triiodothyronine, and so on). Most steroid hormones have names that end in –one, –ol, or –oid (testosterone, aldosterone and other mineralocorticoids, cortisol and other glucocorticoids, and so on). This is not exhaustive, but may help you identify the chemistry of a hormone on Test Day.

MCAT Concept Check 5.1:

Before you move on, assess your understanding of the material with these questions.

1. Compare and contrast peptide and steroid hormones based on the following criteria:

Peptide Hormones

Steroid Hormones

Chemical precursor

Location of receptor

Mechanism of action

Method of travel in the bloodstream

Rapidness of onset

Duration of action

2. How are amino acid-derivative hormones synthesized?

3. What is the difference between a direct and a tropic hormone?

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Anatomy of PNECs

Distribution and population in the airways

Boers et al. (1996) described the distribution and populations of PNECs in adult humans: chromogranin-A (CgA) + (Box 1) PNECs account for 0.41% of all epithelial cells in the conducting airway, but are absent from the alveoli. Recent single-cell RNA sequencing (scRNA-seq) analyses found that PNECs account for 0.01% of all lung cells (Travaglini et al., 2020). Owing to the extensive size of the human lung relative to the small amount of PNECs, determining their lung-wide distribution is rather difficult. Therefore, small mammals – including mice – represent ideal models for obtaining the entire picture of PNEC distribution throughout the tracheobronchial tree, mostly owing to the size advantage for imaging. As revealed by scanning electron microscopy, NEBs form crater-like pits, which are aligned with microvilli and exposed to the airway (Cutz et al., 1978).

NEBs frequently populate diametrically opposed positions to the bifurcation points of branching airways (Avadhanam et al., 1997 Kuo and Krasnow, 2015 Noguchi et al., 2015) (Fig. 1). NEBs at branching points are referred to as ‘nodal’ NEBs, whereas NEBs in inter-bifurcation regions are referred to as ‘internodal’. During development, nodal NEBs overcome internodal NEBs moreover, NEBs grow centrifugally, from proximal to distal bronchi. Three-dimensional (3D) geometric analyses showed nodal NEBs at stereotypic positions in the airway branching structures (Noguchi et al., 2015). In rats, the distribution pattern of NEBs, as well as their absolute number, remains unchanged after birth (Avadhanam et al., 1997). This peculiar distribution of NEBs may be optimal for sensing hypoxic conditions and allergens in the airways nonetheless, further studies are still required to understand its significance, as well as the functional differences between nodal and internodal NEBs.

Schematic representation of pulmonary neuroendocrine cells (PNECs), neuroepithelial bodies (NEBs) and their innervation in the airway. In the mammalian lung, PNECs (yellow) localize at airway bifurcation sites (in the circled area and illustrated on the right), forming small clusters called NEBs. The NEB interacts with sensory nerve terminals, with myelinated afferent nerves (yellow and purple) branching and protruding into the NEB. The other sensory nerve (orange) comprises unmyelinated non-vagal immunoreactive nerve fibers originating from the dorsal root ganglia (DRG). Their axons enter the brain and transmit sensory information to the brainstem (green arrows). NEBs can sense CO2, air pressure, O2, H + ions and nicotine, and activate reactions. ATP, adenosine triphosphate CGRP, calcitonin gene-related peptide GABA, gamma-aminobutyric acid JG, jugular ganglion NG, nodose ganglion 5-HT, serotonin.

Schematic representation of pulmonary neuroendocrine cells (PNECs), neuroepithelial bodies (NEBs) and their innervation in the airway. In the mammalian lung, PNECs (yellow) localize at airway bifurcation sites (in the circled area and illustrated on the right), forming small clusters called NEBs. The NEB interacts with sensory nerve terminals, with myelinated afferent nerves (yellow and purple) branching and protruding into the NEB. The other sensory nerve (orange) comprises unmyelinated non-vagal immunoreactive nerve fibers originating from the dorsal root ganglia (DRG). Their axons enter the brain and transmit sensory information to the brainstem (green arrows). NEBs can sense CO2, air pressure, O2, H + ions and nicotine, and activate reactions. ATP, adenosine triphosphate CGRP, calcitonin gene-related peptide GABA, gamma-aminobutyric acid JG, jugular ganglion NG, nodose ganglion 5-HT, serotonin.

PNEC innervation

In 1972, Lauweryns and Peuskens identified innervated PNECs within the intrapulmonary airway epithelium of human infants (Lauweryns and Peuskens, 1972). Further detailed imaging revealed that various types of sensory (afferent) and motor (efferent) nerve fibers connect to PNECs (Lauweryns et al., 1985) (Fig. 1). NEBs are predominantly innervated by vagal nerve fibers originating from cell bodies located in the nodose ganglion, mainly involved in visceral perception (Adriaensen et al., 1998). Several different types of vagal nerves interact with NEBs, including Na + /K + ATPase + , VGLUT + , calbindin-D (28k) + or P2X2/3 + (also known as P2RX2/3 + ) (Box 1) nerves (Adriaensen et al., 2006). These myelinated afferent nerves lose their sheaths right next to NEBs and then branch and protrude into the epithelium (Brouns et al., 2000, 2003). Conversely, unmyelinated non-vagal calcitonin gene-related peptide (CGRP) + (also known as CALCA + ) (Box 1) nerve fibers, which originate from dorsal root ganglia T1 to T6, make contact with the basal pole of pulmonary NEBs (Brouns et al., 2003 Haller, 1992). Calbindin-D (28k) + and CGRP + nerve fibers often make contact with the same NEBs. Unlike calbindin-D (28k) + nerves, CGRP + nerves express vanilloid receptor subtype 1 and respond to capsaicin, suggesting their C-nociceptive nature (Brouns et al., 2003 Baron, 2000). Chang et al. (2015) identified that P2Y purinoceptor 1 (P2RY1 Box 1) is also expressed in the vagal sensory neurons associated with PNECs. The cell bodies of P2RY1 + nerves reside in the nodose/jugular ganglia their axons enter the brain and target the lateral solitary tract to transmit sensory information to the brainstem nucleus of the dorsal respiratory group, which regulates breathing (Speck and Feldman, 1982). Activation of P2RY1 + neurons activates reflective airway defense mechanisms, such as apnea, vocal fold adduction, swallowing and expiratory reflexes (Prescott et al., 2020). The functional relevance of NEBs and P2RY1 + neurons is an intriguing topic for future research. Defining the role of NEB–P2RY1 + communication could lead to a more complete understanding of the link between airway status and physiological reflexes.

NEB innervation increases with advancing gestation, reaching a plateau after birth (Pan et al., 2004). How do NEBs guide the afferent nerve fibers during development? Both solitary and clustered PNECs are innervated in the human lung (Brouns et al., 2003). Because solitary PNECs are still innervated in mutant mice that fail to form NEBs, clustering seems dispensable for innervation (Branchfield et al., 2016). Subsequent research showed that nerve tracks remain close to the epithelium in PNEC-depleted lungs (Sui et al., 2018). PNECs attract nerve terminals and induce their intraepithelial protrusion. Barrios et al. (2017) reported that PNECs express neurotrophin 4 (NT4 also known as NTF4), while innervating nerves express its cognate receptor TrkB (also known as NTRK2). NT4 plays a role in the formation of nerve contacts to the basal side of NEBs and their penetration therein during development however, NT4 ablation does not entirely abolish innervation, suggesting that additional unknown factors contribute to this synapse formation. Aside from identifying these factors, genetic modulation of neuro-PNEC junctions would help to characterize the physiological functions of PNEC innervation.


Infertility is the inability to conceive a child or carry a child to birth. About 75 percent of causes of infertility can be identified these include diseases, such as sexually transmitted diseases that can cause scarring of the reproductive tubes in either men or women, or developmental problems frequently related to abnormal hormone levels in one of the individuals. Inadequate nutrition, especially starvation, can delay menstruation. Stress can also lead to infertility. Short-term stress can affect hormone levels, while long-term stress can delay puberty and cause less frequent menstrual cycles. Other factors that affect fertility include toxins (such as cadmium), tobacco smoking, marijuana use, gonadal injuries, and aging.

If infertility is identified, several assisted reproductive technologies (ART) are available to aid conception. A common type of ART is in vitro fertilization (IVF) where an egg and sperm are combined outside the body and then placed in the uterus. Eggs are obtained from the woman after extensive hormonal treatments that prepare mature eggs for fertilization and prepare the uterus for implantation of the fertilized egg. Sperm are obtained from the man and they are combined with the eggs and supported through several cell divisions to ensure viability of the zygotes. When the embryos have reached the eight-cell stage, one or more is implanted into the woman’s uterus. If fertilization is not accomplished by simple IVF, a procedure that injects the sperm into an egg can be used. This is called intracytoplasmic sperm injection (ICSI) and is shown in Figure 24.22. IVF procedures produce a surplus of fertilized eggs and embryos that can be frozen and stored for future use. The procedures can also result in multiple births.

Figure 24.22. A sperm is inserted into an egg for fertilization during intracytoplasmic sperm injection (ICSI). (credit: scale-bar data from Matt Russell)

Process of Lactation (With Diagram)

In this article we will discuss about the process of lactation, explained with the help of suitable diagrams.

The hormones which influence the development of breasts are:

a. At puberty, it will be estrogen and progesterone. In addition to these, some of the other hormones which are also required are: thyroxine, growth hormone, Cortisol and insulin.

b. During pregnancy, it will be estrogen and progesterone which are secreted in large quantity either from corpus luteum or placenta. Apart from these, the human chorionic somatomammotropin (HCS) secreted by placenta also is responsible for growth of breasts. There is no lactation during pregnancy because, progesterone level is high and it inhibits the release of prolactin.

c. After delivery, since the concentration of progesterone falls earlier than the estrogen, prolactin secretion starts and lactation commences in about 1-3 days. During this phase, suckling is the most effective stimulus that brings about secretion of prolactin.

“The breasts were more skillful at compounding a feeding mixture than the hemispheres of the most learned professors brain”—Oliver Wendell Holmes

Hormones Influencing Lactation:

Suckling of breasts not only brings about release of oxytocin (Fig. 7.21), it will also stimulate the secretion of prolactin. For both the hormonal secretions, it is the neuroendocrine mechanism that is involved.

2. Some of the other hormones influencing lactation are thyroxine, and growth hormone. ACTH and glucocorticoids are necessary for maintenance of milk secretion which is known as galactopoiesis.

Emotional conditions, like cry of the baby and condition reflexes, also play an important role in lactogenesis.

Advantages of Breastfeeding:

1. Infant gets a well-balanced diet.

2. Stimulation of nipple releases oxytocin. Oxytocin brings about involution of uterus and size of uterus is reduced following parturition.

3. During the time of breastfeeding, ovulation is inhibited. This is because prolactin inhibits the release of luteinizing hormone.

4. The infant gets some amount of passive immunity since milk contains some of the antibodies.

5. Since it is directly coming from mammary gland, contamination is less and chances of child suffering from infantile diarrhea is minimized.

ACCacetyl-CoA carboxylase
AgRPagouti-related peptide
AMPKAMP-activated protein kinase
ARCarcuate nucleus
BATbrown adipose tissue
CARTcocaine-and amphetamine-regulated transcript
CNScentral nervous system
FGFfibroblast growth factor
FoxO1Forkhead box O1
GHgrowth hormone
GLP-1glucagon-like peptide 1
GnRHgonadotropin-releasing hormone
IGFinsulin-like growth factor
IGFBPIGF binding factor
IRSinsulin receptor substrate
JAK2Janus kinase 2
LHluteinizing hormone
LHAlateral hypothalamic area
MAPKmitogen-activated protein kinase
MCHmelanin-concentrating hormone
NPYneuropeptide Y
NTSnucleus of the solitary tract
LepRleptin receptor
LepRblong isoform of leptin receptor
PI3Kphosphatidylinositol 3-kinase
PTP1BProtein tyrosine phosphatase 1B
PYYpeptide YY
SF-1steroidogenic factor 1
SHP2SH2-containing protein tyrosine phosphatase 2
SOCS3suppressor of cytokine signaling 3
STAT3signal transducer and activator of transcription 3
TNFtumor necrosis factor
TRHthyrotropin-releasing hormone
TSHthyroid stimulating hormone
UCPuncoupling protein
VMHventromedial hypothalamus
VTAventral tegmental area
WATwhite adipose tissue

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