CHAPTER ONE Endocrinology, Brain and Pituitary Gland Introduction To understand the biology of reproduction, we must first meet the cast of charac- ters involved in this fascinating process. In Chapters 2 and 4, we will study the anatomical components of the female and male reproductive systems. However, you will discover that, to function properly, these systems require chemical instruc- tions. In fact, nearly every aspect of reproductive biology is regulated by internal molecular messengers called hormones. Reproductive hormones signal the repro- ductive structures to grow and mature. For example, as a boy approaches puberty, circulating levels of hormones called androgens rise and cause his reproductive tract to mature. In addition, these hormones induce muscle growth, cause changes in the vocal cords that lower the young man’s voice, and initiate adult patterns of body hair growth. Hormones also regulate the timing of reproductive events. In women, the coordinated release of several female hormones orchestrates ovulation, the release of an egg from the ovary, approximately every 28 days. This chapter introduces you to the endocrine system, focusing on how the brain and pituitary gland regulate reproductive hormones. Your efforts in studying this material will be repaid as you read further in the text, as an understanding of this topic is essential for you to grasp the information in subsequent chapters. Endocrine System There are two kinds of glands in your body. Exocrine glands secrete substances into ducts (tiny tubes) that empty into body cavities and onto surfaces. Examples are the sweat and oil glands of the skin, the salivary glands, and the mucous and diges- tive glands of your stomach and intestines. In contrast, endocrine glands do not secrete substances into ducts, which is why they sometimes are called “ductless glands.” Instead, endocrine cells secrete products, called hormones, which are released into the adjacent tissue spaces. The hormones then enter the bloodstream and are carried to other regions of the body to exert their effects. Hormones are chemical messengers in that certain tissues in the body are signaled by specific hormones to grow or change their cellular activity. The science of endocrinology also includes the study of paracrines. Paracrines are chemical messengers that are produced by endocrine cells and diffuse to act locally on adjacent target cells with the appropriate receptors. Thus, unlike hormones, paracrines are not carried in the bloodstream (Fig. 1-1). 3 4 1 Endocrinology, Brain and Pituitary Gland GnRH GnRH receptor Natural ↑ GnRH FSH, LH = gain of fertility Pituitary cell Pulsatile administration GnRH ↑ FSH, LH = stimulatory gain of fertility agonist Loss of receptors Constant administration GnRH ↓ FSH, LH = Figure 1-1 Endocrine and paracrine regulation. Target cells for hormones and paracrines must have specific receptors on their cell membrane or in their cytoplasm or nucleus to respond to a particular ligand. The endocrine system consists of all the endocrine glands and isolated endocrine cells in the body. Included in this system are the pituitary gland (or hypophysis), pineal gland, gonads (testes and ovaries), and placenta—all organs of primary importance in human reproduction. In addition, the endocrine system includes the thyroid, parathyroid, and adrenal glands, as well as the hormone-secreting cells of the digestive tract, kidneys, pancreas, and thymus. Figure 1-2 depicts these components of the endocrine system. Science of Endocrinology Endocrinology is the study of the endocrine glands and their secretions. Suppose you are an endocrinologist who has an idea that a particular gland has an endocrine function. What would you do to test this hypothesis? A “classical” approach used by early endocrinologists is as follows: (1) remove the gland, (2) observe the effects of gland removal on the body, (3) replacement therapy, which involves administration of a preparation of the removed gland, and (4) observe to see if the replacement therapy reverses the effects of gland removal. If the replacement therapy does reverse the effects, what could you conclude? In the past, the technique of bioassay was commonly used to measure indirectly the amount of a given hormone in glandular tissue or blood. With this method, several different amounts of a purified hormone are administered to animals, and the physiological or anatomical changes in target tissues are measured. In this way, a given degree of biological response can be associated with a given amount of hormone administered. Ideally, the response should increase in proportion to the increasing amounts of hormone administered; that is, a dose–response relationship, or “standard curve,” is obtained. Then, a gland Science of Endocrinology 5 Hypophysis Pineal gland Parathyroid glands (behind thyroid gland) Thyroid gland Trachea Lungs Thymus gland Heart Adrenal glands Kidney Stomach Pancreas Ovaries Scrotum Testes Figure 1-2 Major components of the endocrine system (shown in red). The placenta is not shown. preparation or blood containing an unknown amount of this hormone is admin- istered to other animals, and the biological response obtained is compared to the dose–response relationship. In this way, the amount of hormone in the gland or blood is determined. A more direct and accurate way to measure the amount of a hormone in tissues or in blood is radioimmunoassay. This assay uses an antibody against the hormone of interest and a radioactive tracer for detection and measurement of the hormone. Radioimmunoassay is used to measure blood levels of hormones in humans and other animals, and it has been a valuable tool in reproductive biology and in tests for disorders of the endocrine system. In 1977, Rosalyn S. Yalow received the Nobel Prize in Physiology and Medicine for her development of this technique. Radioimmunoassay is now becoming less popular as sensitive nonradioactive methods have been developed. For example, ELISA assays are used for measur- ing a wide variety of hormones and hormone products. High-performance liquid chromatography techniques coupled with spectrophotometric analyses are used to identify hormones and other regulators in biological fluids. A method used 6 1 Endocrinology, Brain and Pituitary Gland commonly to measure mixed steroids in plasma or urine samples is gas chro- matography with mass spectrometry. Endocrinologists studying the structure and function of endocrine cells use techniques such as immunocytochemistry and immunofluorescent staining of cells, imaged with the confocal microscope. Genetic engineering has revolutionized endocrine studies. One major area is the development of probes to measure mRNA production to determine when a gene is activated or shut down by a hormone. Genetically engineered knock- out mice and knock-in mice are widely used to investigate problems of sexual differentiation and in behavioral studies of mice and rats. Yeast cells genetically engineered to contain genes for human estrogen receptors, with the help of reporter genes, can be used in assays for measuring estrogenic activity. These new tools have allowed endocrinologists to make advances in our understanding of normal human reproductive physiology, as well as of reproductive disorders such as breast cancer. Hormones Hormones have diverse molecular structures. Some hormones are proteins or smaller polypeptides or peptides. These kinds of molecules are made up of chains of amino acids containing oxygen, carbon, hydrogen, and nitrogen. Other hormones are amines, which are derivatives of amino acids; these are formed from single amino acids that have been altered chemically. Some hormones are derived from fatty acids. Steroid hormones are molecules derived from cholesterol. Male sex hormones (androgens) and female sex hormones (estrogens and progestogens) are examples of steroid hormones. Androgens are substances that promote the development and function of the male reproductive structures. Estrogens stimulate the maturation and function of the female reproductive structures. Progestogens (or progestins) are substances that cause the uterus to be secretory. Receptors Even though all body tissues may be exposed to hormones, only certain target tissues are responsive to a given hormone. Cells of these target tissues have specific hormone receptors on their surface membrane, or in their cytoplasm or nucleus, that bind to a given hormone. A molecule (such as a hormone) that binds to a receptor is sometimes referred to as its ligand. Protein and peptide hormones, including gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL), bind to receptors embed- ded in the cell membrane of responsive cells. These receptors are large protein molecules that typically have three major regions, or domains (Fig. 1-3). The hormonal signal is received when the ligand attaches to a ligand-binding site in the extracellular domain, a portion of the receptor that sticks out beyond the cell. A transmembrane domain anchors the receptor within the plasma membrane. Finally, the intracellular domain is an extension of the receptor protein within the cell cytoplasm. Binding of the ligand to its receptor causes a conformational (shape) change in the receptor. This triggers a biochemical change in the cyto- plasm of the cell, causing the release of a second messenger, the first messenger being the hormone itself (Fig. 1-4). Examples of second messengers include cAMP Receptors 7 NH2 Ligand-