Biomedicine and Health: Hormonal Regulation of the Body

Introduction

Hormones are chemicals produced by the body that act as messengers between cells. There are many different kinds of hormones that stimulate a multitude of activities in the body. Most are secreted by glands that are part of the endocrine system, although organs such as the stomach, heart, ovaries, testes, and pancreas produce hormones as well. Once secreted, hormones then travel through the blood to the target cells.

Some hormones affect many different kinds of cells; others only work on one type. Conversely, one type of cell may have the ability to respond to multiple hormones. Through these complex interactions, hormones help the body maintain homeostasis, the internal balance of systems that maintains life. Hormones are also part of the body's long-term response to change and threats, as opposed to the short-term response provided by the nervous system.

Historical Background and Scientific Foundations

Before the middle of the nineteenth century, even the most rudimentary functions of the endocrine system were not understood. Hormones had not yet been discovered, and the idea that one organ or structure might influence another was totally incomprehensible. The French physiologist Claude Bernard (1813–1878) was the first to use the term “internal secretion” to describe substances emitted by the liver. Bernard knew nothing of hormones, and his term was subsequently adopted to describe the release of any substance from a cell into the blood. However, the idea that internal organs could secrete invisible substances would provide impetus to future discoveries.

In 1855, Thomas Addison (1793–1860) made one of the next important discoveries about the endocrine system. He described a syndrome in which the skin darkened and patients experienced fatigue, nausea, and vomiting. The French-British physiologist Charles-Édouard Brown-Séquard (1817–1894) later reproduced this condition by removing an animal's adrenal glands, proving that it was always fatal. Though not clear at the time, this syndrome, now called Addison's disease, results from a lack of hormones, particularly cortisol, from the adrenal glands. It is a serious condition because the adrenal hormones affect many tissues and chemicals in the body, including digestion, immune response, electrolyte levels, bone formation, blood pressure, inflammatory response, and urinary function. In 1893, the physician George Oliver (1841–1915) proved that administration of cortisol raised blood pressure.

Brown-Séquard also examined the function of the male testes by using an extract made from animal testicles. Already in old age, he ingested the extract and found it to have rejuvenating properties. Today, we know that this is because the substance contained testosterone, the male sex hormone. Brown-Séquard then went on to claim that every organ in the body had curative properties if consumed as a medicine. Though not true for every bodily organ, this practice does work when the endocrine glands are used; that is, Brown-Séquard's original idea was sound, but he extended it beyond its limits. This type of treatment, known as “organotherapy,” eventually provided treatments for many previously incurable diseases.

One of the next endocrine organs to be examined scientifically was the thyroid. The thyroid is a large gland located in the neck that secretes thyroid hormones. These hormones regulate the metabolism of all the cells in the body. An underactive thyroid produces too little thyroid hormone and can cause changes in digestion and metabolism, leading to fatigue and weight gain. Nerve and muscle function is also altered, causing weakness. Conversely, an overactive thyroid produces too much thyroid hormone and can cause weight loss, increased hunger and thirst, heart arrhythmia, and anxiety. In 1891 British physiologist Victor Horsley (1857–1916) and physician George Murray (1865–1939) proved that hypothyroidism, or underactive thyroid, can be treated by extracts from healthy thyroid glands. Later, Oliver and English physiologist Edward Sharpey-Schafer (1850–1935) tested the effects of thyroid, pituitary, and adrenal extracts on blood pressure.

At this point it was clear that endocrine glands produced substances that altered bodily functions. The nature of these substances was still unknown, however. Apart from Brown-Séquard's rejuvenating extract, the hormonal potential of the ovaries and testes was also still unrealized. British physiologist Ernest Starling (1866–1927) and his brother-in-law and fellow scientist William Bayliss (1860–1924) changed this. They began to investigate the connections between the duodenum (the first part of the small intestine immediately connected to the stomach) and the secretions of the pancreas.

It was known that when acid was introduced into the duodenum, the pancreas then emitted secretions. The previous belief was that the nerves were responsible for sending a signal from the duodenum to the pancreas, possibly via the brain. Starling and Bayliss systematically severed the nerves leading to both the duodenum and the pancreas. They then introduced acid into the duodenum and observed that pancreatic secretions were produced normally. Subsequently, they isolated a substance from the cells of the duodenum and injected

it into a dog, yet again producing secretions from the pancreas. They named this substance “secretin,” the first hormone ever discovered.

Starling and Bayliss continued their exploration of secretin and its production in the intestine. They determined that the hormone must be secreted into the blood for it to create an effect in an organ so distant from the source. Furthermore, they determined that most hormones are effective for a short time and must be replenished by continual production. They also made investigations into its chemical structure. By 1905 Starling had determined that the body has two methods of control: nervous and chemical. This is the same year he first used the word “hormone” to refer to secretin and other chemicals that act on cells distant from their site of production. In one of his lectures of the same year, he referred to secretions of the thyroid, testes, and ovaries as hormones.

IN CONTEXT: INSULIN

In January 1922, Canadian physician Frederick Banting (1891–1941) and his medical student assistant Charles Best (1899–1978) administered an anti-diabetic hormone they had isolated from the pancreas of a calf and had named “isletin” to Leonard Thompson, a fourteen year-old patient dying of diabetes in Toronto General Hospital. This marked the first time insulin was administered to a human. Thompson's blood sugar levels, initially high enough to produce diabetic ketoacidosis and coma, dropped dramatically after the insulin was injected. Two weeks were necessary for the scientists to prepare an additional insulin extract, and with several injections, Thompson's blood sugar levels stabilized and he was eventually released from the hospital.

The Nobel Prize for Medicine or Physiology in 1920 was awarded to Banting for the discovery of insulin, along with the Scottish physiologist John Macleod (1876–1935), who had given Banting laboratory space. Banting felt strongly that Best should have been recognized by the Nobel committee as well, and shared half of his prize money with Best. Upon learning this, Macleod shared his prize with Canadian biochemist James D. Collip (1892–1965), who helped purify the insulin extract. For some years afterward, the four men privately feuded over the essential nature of each of their roles in the discovery. By 2000, experts estimated that over 100 million people worldwide with diabetes received insulin injections to maintain healthy glucose levels in their blood.

This work spurred research into the body's many other kinds of hormones. Today, it is known that most glands are part of the endocrine system. They produce hormones, which are released within the body and signal other groups of cells to change their behavior. Not all glands are part of the endocrine system. Some glands, including sebaceous and mammary glands, do not emit their products into the bloodstream like endocrine glands do. These are known as exocrine glands, and their secretions are carried through ducts, usually to the surface of the body.

Most hormones are either proteins or are structurally related to proteins. The remaining hormones, including the sex hormones, are classified as steroids. Regardless of their structure, hormones are extremely powerful; only minute amounts are required to induce an effect in the target cells. Because they are carried by the blood, it is easy for hormones to come in contact with most of the cells in the body. This is one reason they are able to produce such potent reactions. However, not all hormones are able to affect all types of cells. This is because each hormone must join with the right kind of receptor to have an effect. Just like a lock and key, if the right kind of receptor is not available on a cell, the hormone will be unable to affect it.

Because hormones are very potent, their amount in the blood must be strictly controlled. Many glands are sensitive to the hormone they excrete. Therefore, when levels are low they produce more, and when levels are high they produce less. Sometimes the release of one hormone stimulates the release of another. For example, the hypothalamus region of the brain releases thyroid-stimulating hormone, which then causes the thyroid to release thyroid hormones. In other cases, the release of hormones is triggered by nerve impulses.

The pituitary gland, sometimes thought of as the body's “master gland,” is located within the skull. It receives nerve impulses from the brain, as well as hormone signals from the hypothalamus. The pituitary releases growth hormone, which controls the body's growth and development. It also secretes hormones that stimulate the adrenal glands, hormones that regulate kidney function, and gonadotropic hormones that regulate the growth and development of the reproductive system. A nearby gland called the pineal gland secretes melatonin, which, among other functions, regulates sleep.

Sometimes, the production of a hormone needs special ingredients. The thyroid requires iodine from the diet so that it can form thyroid hormones. Without iodine, the thyroid becomes enlarged, forming what is known as a goiter. Resting on the thyroid is the parathyroid gland, which forms a hormone that regulates calcium in the blood. Calcium is important in the contracting of muscles. Without enough parathyroid hormone, too little calcium in the blood can lead to muscle spasms.

To form sex hormones, the body requires cholesterol, some of which is consumed in the diet and the rest formed by the liver. There are many types of sex hormones, broadly divided into the androgens or male sex hormones, and the estrogens and progestagens, the female sex hormones. The sex hormones are responsible for the development of the reproductive systems in males and females, the development of secondary sex characteristics, and the changes that maintain pregnancy and the menstrual cycle. Most sex hormones are produced in the ovaries and testes, but small amounts of testosterone and estrogen are produced by the adrenal glands, located on the kidneys.

The adrenal glands are divided into two distinct parts, the exterior cortex and the interior medulla. Each part secretes different hormones with different functions. Steroid hormones known as mineralocorticoids are secreted by the adrenal cortex to regulate fluids and sodium in the body. Cortisol and its related hormones raise blood glucose in response to threats, and also affect many other bodily processes. The adrenal medulla produces epinephrine and norepinephrine, which help the body respond to stress. Also known as adrenaline, epinephrine is responsible for the “fight-or-flight response” to acute stress or fear.

The pancreas secretes hormones and enzymes necessary for digestive and metabolic processes. Part of the organ is considered to be part of the exocrine system, producing digestive enzymes in response to the hormone secretin. Its other major part, known as the Islet of Langerhans, secretes two different hormones in response to changing blood glucose levels. Glucagons are produced when blood glucose levels are low, causing them to rise to a normal level. Insulin is produced when blood glucose levels are high, causing them to fall back to normal concentrations. Maintenance of blood glucose is very important; short-term aberrations in either direction can be deadly, and long-term high glucose can lead to serious cardiovascular disease.

Modern Cultural Connections

Many of the body's hormones are still undiscovered. Research into the biochemical function of the body continues to uncover new types of hormones and the responses they create. One of the most interesting areas of research is the study of how the body processes energy, stores fat, and signals hunger. The increasing obesity rate is driving new research, hoping to find new mechanisms to control and decrease excess body fat. Maintaining the correct levels of all hormones is critical to maintaining homeostasis and general health. Without appropriate hormone balance, the systems of the body are disrupted, leading to disease or even death. Scientists hope that increased understanding of the body's hormonal controls will result in the continuing development of new treatments for diseases.

In 2002, preliminary results from a major study conducted by the National Institutes of Health resulted in a dramatic shift in the way hormone-replacement therapy for post-menopausal women was viewed. Long perceived as having a protective effect against heart disease, key components of the Women's Health Initiative were halted early after evidence emerged that estrogen-progestin and estrogen alone hormone replacement therapy actually increased rates of heart disease, strokes, blood clots, and certain cancers in post-menopausal women. As a result, doctors wrote 20 million fewer prescriptions for hormone replacement therapy in 2003. The following year, breast cancer cases in the United States dropped by 7%. Although research has not definitively proven that the drop in breast cancer was due to the drop in hormone replacement therapy use, many experts link the two findings.

Later research has shown that younger women, those just entering the menopausal years, could benefit from hormone replacement therapy. One joint study analysis by scientists at Cornell and Stanford Universities showed that menopausal women in their fifties who take hormone replacement therapy have an overall lower death rate, especially from cardiovascular disease, than women of the same age who do not take hormone replacement therapy. In light of multiple studies with seemingly conflicting findings, the National Institutes for Health issued guidelines in 2003 for women and their physicians about hormone replacement therapy. Essentially, the guidelines recommend that hormone replacement therapy should not be taken solely for preventing heart disease, and that the lowest effective dose of replacement hormones should be taken for the shortest time possible in women who need them for relief of hot flashes, insomnia, bone density loss, or other symptoms associated with the body's reduced production of estrogen during and after menopause.

IN CONTEXT: HORMONES AND SOCIAL REVOLUTION

In 1945, an idea presented by American endocrinologist Fuller Albright (1900–1969) planted the seeds of an impending social revolution. Allbright proposed the possibility of “birth control by hormone therapy.” After hearing of what became known as Albright's Prophecy, American Planned Parenthood founder Margaret Sanger (1879–1966), then seventy years old, set out to inspire the development of an oral contraceptive. Sanger and her wealthy American friend Katharine McCormick (1875–1967), also in her seventies, approached research biologist George Pincus (1905–1967) of the Worcester Foundation for Experimental Biology with the task in 1948. Two years later, funded by McCormick, Pincus began the research, which led to the introduction of a hormonal oral contraceptive (birth control pill). Ultimately, the birth control pill led to the first generation of women able to separate sexuality from reproduction and plan the size of their families. This led to the sexual revolution of the 1960s, the women's movement of the 1970s, and an influx of women into the workplace.

Primary Source Connection

Persistent organic pollutants, also called POPs, are chemicals that remain in the environment for extended periods, accumulate in man and animals through the food web, and pose a risk to the health of both animals and the environment. The United Nations Environmental Program (UNEP) monitors the accumulation of POPs throughout the world and recommends ways to reduce the release of POPs into the environment. In the study excerpted below, researcher Lawrence M. Schell discusses how several POPs affected the growth and development of young people of the Mohawk Akwesasne nation.

Lawrence M. Schell is a professor of sociology at the State University of New York at Albany and is the director of the Center for the Elimination of Minority Health Disparities there.

EFFECTS OF POLLUTION ON HUMAN GROWTH AND DEVELOPMENT: AN INTRODUCTION

Pollution is a worldwide problem and its potential to influence the physiology of human populations is great. Studies of human growth and development in relation to pollution have increased in number and quality since the mid-twentieth century. Many studies have found that some pollutants have detrimental effects on human growth, particularly prenatal growth. The heavy metal, lead, is commonly found in human populations and is related to smaller size at birth and studies have reported decrements that range up to about 200 grams. Noise stress from transportation sources also is related to reduced prenatal growth with somewhat smaller decrements reported. Studies of humans exposed to polychlorinated biphenyls, one of the persistent organic pollutants, have reduced size at birth, advanced sexual maturation and altered hormone levels related to thyroid regulation. Thus different pollutants exert effects through different physiological pathways. However, some studies have not observed these effects, which indicates that the situation is complex and requires further study with better study designs. Determining the effects of pollutants on human physiology and growth is difficult as it requires fairly large numbers of subjects who are not purposely exposed but for whom exposure can be measured. These effects of pollutants and the mechanisms of effect require further study to understand and, it is hoped, to blunt or block any detrimental effects on human health and well-being….

Persistent Organic Pollutants: Polychlorinated Biphenyls

Persistent organic pollutants (POPs) are a group of compounds produced purposely or accidentally by industrial processes. They include a variety of pesticides and herbicides such as hexochlorobenzene (HCB), mirex, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), polychlorinated biphenyls (PCBs) and polybromated biphenyls (PBBs), and dioxin (2-3-7-8 tetrachlorodibenzo-p-dioxin, (TCDD)). They are lipophilic and are concentrated in adipose tissue. They bioaccumulate up the food chain and many are metabolized slowly over years and decades. Breast milk contains concentrated POPs….

[S]cientists have investigated many populations for the presence of PCBs and other POPs, and have discovered low levels of POPs in all populations studied, even in very remote arctic populations in North America (Tenenbaum, 1998)….Exposure to POPs is extensive because they have entered the food chain and are very persistent. Most human exposure is through ingestion of fish, meat, eggs, and dairy products including milk and butter. Because POPs are lipophilic [literally, “fat-loving”] and bioaccumulate, they are concentrated in animals that consume other animals or that are fed fats from other animals. Thus, cattle and farm raised salmon may have higher levels of POPs than free-living populations, and free-living animals high on the food chain such as whale, walrus, and polar bear, may carry high levels of POPs. In addition, POPs are transferred from mother to fetus across the placenta, and from mother to infant through lactation. POPs also can be absorbed through the dermis, and inhalation is an additional route of exposure. POPs can be carried from industrial areas by winds high aloft to remote areas such as the Arctic and contaminate food there.

Many PCBs are very persistent in the environment and can resist metabolism leading to long-term storage in fat tissue. These properties depend on the form of the molecule. PCBs can take a large variety of forms, or congeners, depending on how many carbons are substituted with chlorines and where the substitutions occur. Some congeners of PCBs persist in people and the environment for decades…. In general, PCBs are suspected of causing a wide variety of physiological changes that may in turn contribute to health problems involving the endocrine, reproductive, immune, nervous and cardiovascular systems.

To investigate the effects of low-level exposure to PCBs and other toxicants, we began a study of Mohawk Indian youth 10–16.9 years of age. The youth were all members of the Akwesasne Mohawk Nation. The Nation straddles the St. Lawrence River and occupies territory in New York State (US), and in Quebec and Ontario (Canada). Exposure at Akwesasne occurred when industries located on the St. Lawrence River in the 1950s contaminated the environment with PCBs through improper disposal practices. Fish and game absorbed the PCBs. Customary food sources for the Akwesasne community include locally caught fish, and ingestion of fish was a major route of exposure for adults and children. Newborns were through lactation. Postnatal exposure also occurred through the consumption of contaminated fish and game. In the mid-1980s local and state departments of health advised the population to avoid consumption of locally caught fish, and levels of PCBs have fallen since then (Fitzgerald et al., 1998, 1999). However, persistent PCBs remain in adults and children at Akwesasne, although at levels lower than occurred in Yusho poisoning.

Our research at Akwesasne includes investigation of growth and maturation, levels of sex steroids and thyroid hormones, as well as cognitive and behavioral characteristics. The 10–16.9 year age range of participants allowed the study of growth during a period of rapid growth, as well as sexual maturation including changes in sex steroids while having relatively constant levels of thyroid hormones. Participants were sufficiently mature to follow instructions for sensitive testing of cognition and behavior. This holistic approach involves the collection of a great deal of data and some of these data have been analyzed….

We have examined the effect of several pollutants, including PCBs, on the timing of menarche [beginning of menstruation] (Denham et al., 2005). We performed probit and logit analyses on presence or absence of menarche. In our analysis we found that menarche was more likely to have occurred among same-aged girls with higher PCB burdens. Furthermore, these associations were specifically seen for a group of four potentially estrogenic PCB congeners, but were not found when tested with groups of antiestrogenic or enzyme-inducing congeners (Denham et al., 2005). At the lowest level of the estrogenic PCB group, 33% of 12-year-old Mohawk girls were predicted to have reached menarche when controlling for socioeconomic status and other toxicant burdens (lead, mercury, HCB, p, p-DDE, mirex), whereas at the geometric mean 69%, and at the highest PCB value 98% of 12-year-old girls were predicted to have reached menarche. This effect was observed among girls with toxicant burdens comparable to other populations exposed at background levels.

We also have examined the relationship of toxicants to levels of thyroid hormones. Thyroid hormones are essential for maintaining normal rates of metabolism, growth and development, and cognitive performance. Our initial analysis of 115 boys and girls indicated that some PCBs were related to thyroid hormones and activity. A group of the more highly chlorinated PCB congeners was positively and significantly associated with thyroid stimulating hormone (TSH) and was negatively associated with thyroxine. These results were observed in a multivariale analysis controlling for other variables, such as blood lipids and other toxicants (Schell et al., 2004). A high level of TSH is diagnostic of hypothyroidism. Although we did not find a significantly elevated occurrence of this disease, we did find a shift in the distribution of TSH indicating that PCBs had affected thyroid physiology in this population. Higher TSH levels in conjunction with lower levels of thyroxine and free thyroxine suggest that the hypopituitary thyroid axis is functioning to maintain normal thyroid gland activity and related functions. Other toxicants were not so clearly related to thyroid hormones or TSH….

In summary, the data on PCBs reported to date suggest that the greatest risks to development are associated with exposure during the prenatal period. The effects reported on growth postnatally suggest possible impairment during a critical period of neuroendocrine or other central nervous system development.

Lawrence M. Schell

schell, lawrence m., “effects of pollution on human growth and development: an introduction” journal of physiological anthropology 25 (2006): 1, 103–112.

See Also Biomedicine and Health: Embryology; Biomedicine and Health: Immunity and the Immune System; Biomedicine and Health: Physiology; Biomedicine and Health: The Brain and Nervous System.

bibliography

Periodicals

Henderson, John. “Ernest Starling and ‘Hormones’: An Historical Commentary.” Journal of Endocrinology 184 (2005): 5–10.

Schell, Lawrence M., “Effects of Pollution on Human Growth and Development: An Introduction” Journal of Physiological Anthropology 25 (2006): 1, 103–112.

Web Sites

BBC News. “Where We'd Be Without Hormones.” January 24, 2005. http://news.bbc.co.uk/2/hi/health/4194589.stm (accessed February 9, 2008).

Middle Tennessee State University. “Mechanisms of Hormone Action.” February 25, 2006. http://www.mtsu.edu/̃jshardo/bly2020/hormonal_regulation/mechanism.html (accessed February 9, 2008).

U.S. National Library of Medicine. U.S. National Institutes of Health. “Hormones.” January 31, 2008. http://www.nlm.nih.gov/medlineplus/hormones.html (accessed February 9, 2008).

René Nougayrède