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 RECEPTORS 5
used to identify hormones and other regulators in bio- Hormone A Hormone B
logical fluids. A method commonly used 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 immu-
nofluorescent staining of cells, imaged with the confocal
microscope.
Genetic engineering has revolutionized endocrine Target cell for Target cell for Target cell for
studies. One major area is the development of probes to hormone A hormones A and B hormone B
measure mRNA production to determine when a gene is FIGURE 1.3 Target cells for hormones must have specific receptors
activated or shut down by a hormone. Genetically engi- on their cell membranes or in their cytoplasm to respond to a particular
neered knockout and knock-in mice and rats are widely ligand.
used to investigate problems of sexual differentiation and
in behavioral studies. Yeast cells genetically engineered
to contain genes for human estrogen receptors, with the receptor molecules interact (bind), and the bound recep-
help of reporter genes, can be used in assays for mea- tor transmits the molecular message within the cell to
suring estrogen activity. These new tools have allowed exert a biological response.
endocrinologists to make advances in our understanding
of normal human reproductive physiology, as well as of
Receptors for Protein Hormones
reproductive disorders such as breast cancer.
Protein and peptide hormones, including the repro-
ductive hormones gonadotropin-releasing hormone
HORMONES (GnRH), follicle-stimulating hormone (FSH), luteiniz-
ing hormone (LH), and prolactin (PRL), bind to recep-
Hormones have diverse molecular structures. Some tors embedded in the cell membrane of responsive
hormones are proteins or smaller polypeptides or pep- cells. These receptors are large protein molecules that
tides. These kinds of molecules are made up of chains typically have three major regions, or domains (Figure
of amino acids containing oxygen, carbon, hydrogen, 1.4). The hormonal signal is received when the ligand
and nitrogen. Other hormones are amines, which are attaches to a ligand-binding site in the extracellular domain,
derivatives of amino acids; these are formed from a portion of the receptor that sticks out beyond the cell.
single amino acids that have been chemically altered. A transmembrane domain anchors the receptor within the
Some hormones are derived from fatty acids. Steroid plasma membrane. Finally, the intracellular domain is an
hormones are molecules derived from cholesterol. extension of the receptor protein within the cell cyto-
Male sex hormones (androgens) and female sex hor- plasm. Binding of the ligand to its receptor causes a con-
mones (estrogens and progestins) are examples of ste- formational (shape) change in the receptor. This triggers a
roid hormones. Androgens are substances that promote biochemical change in the cell’s cytoplasm, causing the
the development and function of the male reproduc- release of a second messenger, the first messenger being
tive structures. Estrogens stimulate the maturation and the hormone itself (Figure 1.5). Examples of second mes-
function of the female reproductive structures. Pro- sengers include cAMP and Ca2+. This “translation” of
gestins (or progestogens) are substances that cause the the hormonal message to the interior of the cell is called
uterus to be secretory. signal transduction. Because signal transduction usually
involves turning on or off a series of enzymes, a few mol-
ecules of a hormone can be amplified to alter thousands
RECEPTORS of molecules inside the cell (Figure 1.6). Response to a
protein/polypeptide hormone can occur in seconds or
Even though all body tissues may be exposed to hor- minutes after receptor binding.
mones, only certain target tissues are responsive to a The biological activity of a given hormone in a particu-
given hormone. Cells of these target tissues have specific lar tissue depends on the local concentration of the hor-
hormone receptors on their surface membranes, or in mone. In addition, the hormone’s activity depends on the
their cytoplasm or nucleus, that bind to a given hormone number of receptors for that hormone that are present.
(Figure 1.3). A molecule (such as a hormone or drug) that Cells can upregulate (gain) or downregulate (lose) receptors,
binds to a receptor is referred to as its ligand. Receptors and the timing of some reproductive functions (such as
are proteins that can accurately recognize a ligand from growth of the ovarian follicle) is dependent on the change
the pool of molecules in its environment. Ligand and in number of hormone receptors present. Upregulation

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

6 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

NH2

Ligand-
binding
domain
Extracellular
Hormone domain

Cell Transmembrane
membrane domain

Intracellular
domain

HOOC

FIGURE 1.4 Representation of a cell surface receptor molecule showing the ligand-binding domain (green) as a portion of the extracellular
domain. The transmembrane domain spans the plasma membrane of the cell, and the intracellular domain extends into the cytoplasm.

Hormone
Receptor
Hormone
Activated Plasma
G protein membrane
G protein
AC
AC active
GTP Adenylate inactive
Membrane- cyclase
bound
ATP cAMP
receptor
ATP
cAMP
PKA
inactive PKA
active

Protein
kinase
Enzyme Enzyme
inactive active

Cellular response

FIGURE 1.5 Mechanism of action of a peptide hormone. The l­igand

binds to a cell surface receptor. Usually this activates a G protein, caus-
ing release of a second messenger (here, cAMP). The signal is transduced
to the cell i­ nterior, where it modifies the activity of cytoplasmic enzymes.

can occur when a gene encoding a receptor is activated, FIGURE 1.6 Signal amplification of a peptide hormone. Binding
of a peptide hormone to its membrane receptor activates a series of
resulting in the production of additional receptor proteins.
biochemical reactions inside the cell. Each step can be amplified, thus
After binding to a peptide ligand, a bound receptor may turning a small stimulus into a large response. AC, adenylate cyclase;
be internalized into the cell and targeted for degradation PKA, protein kinase A.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 Receptors 7

Receptor Ligand
Plasma membrane

Matured
endosome

Early
Recycling endosome
of receptors

Degradation
in lysosome

Dissociation
and sorting

FIGURE 1.7 Receptor-mediated endocytosis. After a peptide hormone delivers its message to a target cell, the signaling must be ended.
Groups of ligand-bound cell surface receptors pinch off as a small vesicle and are internalized into the cell. In the cytoplasm, the ligand/receptor
complex is dissociated. The hormone is degraded and the receptor may be recycled back to the cell surface.

(downregulation) or recycled back to the plasma mem- activate or inhibit transcription; the presence of differ-
brane for further use (see Figure 1.7). ent cofactors in different cells helps explain why the
same hormone can have differing effects on various cell
types. Because steroids alter gene expression, and tran-
Receptors for Steroid Hormones scription and translation of a protein require at least
Unlike protein and peptide hormones, which must 30 min, the effects of steroids on the body are typically
act at the cell surface, steroid hormones (such as estro- slow (but long lasting). Whereas protein and peptide
gen, testosterone, and progesterone) are lipid soluble hormones often act within minutes, the effects of ste-
and thus can easily pass through the phospholipid roids are measured in terms of hours or days. Recent
bilayer of the plasma membrane. Steroid receptors are evidence indicates that some steroids also act through
located within the cytoplasm or the nucleus of target cell-surface receptors.
cells. When a steroid hormone binds to its receptor One might expect that each hormone has its unique
(Figure 1.8), the steroid/receptor complex undergoes receptor, resulting in equal numbers of hormone and
a conformational change that exposes a DNA-binding receptor types. This is not necessarily the case. Many
domain. This part of the receptor binds to a regula- hormone receptors, especially steroid receptors, lack
tory region of a steroid-responsive gene, turning on or specificity and can accept more than one type of ligand
off transcription of the gene. Bound steroid receptors molecule. Theoretically, any molecule that can achieve
interact with cofactors, which are nuclear proteins that a three-dimensional fit into the ligand-binding domain

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

8 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

Secretion and Metabolism of Hormones

Steroid hormone
After a hormone molecule is synthesized within an
endocrine cell, it must be released from the producing
Receptor cell before exerting a physiological effect. Because they
can easily pass through biological membranes, steroid
hormones are not stored but are released at the rate at
which they are synthesized. In contrast, synthesis and
secretion (release) are often separately controlled steps
for peptide hormones. They may be stored in secretory
Receptor-
hormone
vesicles that can then fuse with the cell’s plasma mem-
complex brane, releasing the hormones into the extracellular
Translation
environment.
Once in the bloodstream, hormones may find their
target receptors to exert physiological effects, or they
may be metabolized (chemically altered or degraded)
Transcription Protein before reaching their targets. Peptide hormones are eas-
mRNA ily metabolized by enzymes in the blood plasma, and
both peptide and steroid hormones are metabolized by
FIGURE 1.8 Mechanism of action of a steroid hormone. Lipid- the liver and excreted by the kidneys. Metabolism can
soluble steroids enter the cell cytoplasm by diffusion and bind to
­receptors in the cytoplasm or nucleus. The steroid/receptor complex
also occur in target cells. Notably, target tissue metabo-
binds to regulatory regions of DNA, affecting the expression of specific lism may convert a steroid hormone to a more biologi-
steroid-responsive genes. cally active form, to a steroid with weaker activity, or to
an inactive metabolite.
The lifespan of a hormone molecule is limited and is
of a steroid receptor can interact with that receptor. For typically described as the molecule’s half-life, the time it
example, there are three major naturally occurring estro- takes for the blood plasma concentration of an amount
gens, each of which can activate a single estrogen recep- of secreted hormone to be reduced to half. The half-life
tor. Because of differences in their chemical structures, of peptide hormones is usually in the range of minutes,
however, they bind to the estrogen receptor with differ- whereas the half-life of steroids may be hours.
ent affinities (strengths). Estradiol has greatest affinity Thus, to understand the action of a hormone on its
for the estrogen receptor; for this reason it is considered target, we must know the local concentration of the hor-
a potent or “strong” estrogen. Estriol and estrone are mone, which is affected by the rate of its synthesis and
“weak” estrogens. Estrone binds to the estrogen recep- secretion, its half-life, and transport through plasma or
tor about 10% as well as does estradiol, and estriol binds extracellular fluid to its target cell; the proportion of hor-
only 1% as efficiently. mone available to receptors, which in the case of steroid
hormones is influenced by the plasma concentration of
binding proteins; and the number of unbound receptors.
Sex Steroid Binding Globulins
Although peptide hormones can travel freely in
plasma, gonadal steroid molecules are quickly attached SYNTHETIC HORMONES
to sex-steroid binding globulins in the blood after being
secreted into the circulation. Hitching a ride on these cir- Molecules that activate hormone receptors, thus mim-
culating proteins allows the lipophilic steroids to circu- icking the natural hormones produced by endocrine
late more freely in the aquatic bloodstream. The binding glands, occur in our environment and in the food we
proteins release only a certain number of steroid mol- eat. For example, in addition to the naturally occurring
ecules at a given time, freeing them to leave the blood- human estrogens, exogenous compounds (from a source
stream and travel to target cells. Typically only a small outside our bodies) can have estrogenic effects. Weak
proportion of the secreted steroid (2–3% in the case of estrogens synthesized by plants, called phytoestrogens,
estradiol) is free in the plasma. The availability of steroid can bind to estrogen receptors. One of these phytoestro-
hormones to target cells is regulated by the concentra- gens is genistein, found in the soybean plant. Scientists
tion of carrier proteins, whose levels change under cer- have also become aware of numerous man-made chemi-
tain conditions such as pregnancy and obesity. The ratio cals with estrogenic effects. Many of these xenoestrogens
of free to bound steroid is an important factor in the bio- are pesticides related to DDT, or industrial chemicals
logical activity of a steroid hormone. such as those used in the synthesis of plastics. An

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 Synthetic Hormones 9
active search is underway to identify these compounds Tamoxifen is one of the antiestrogens developed to
and determine their possible effects on human health and inhibit the growth of estrogen-dependent breast can-
impacts on wildlife (see Box 2.2 “Xenoestrogens and cers. This compound effectively blocks the estrogen
Breast Cancer” in Chapter 2). receptor’s ligand-binding site and thus prevents natural
The pharmaceutical industry has taken advantage estrogen from stimulating the growth of breast tumors.
of the estrogen receptor’s lack of specificity to synthe- However, because estrogen also maintains bone den-
size a wide variety of artificial estrogens. These analogs sity, it was feared that women taking tamoxifen would
are compounds that are chemically similar to estrogen. develop brittle bones. Surprisingly, the drug did not
Analogs that mimic estrogen-like effects are called have this deleterious effect; in fact, tamoxifen actually
agonists. Some analogs, however, bind to the estrogen helped maintain bone density. Thus, the drug acts as
receptor without eliciting an estrogen-like cellular an estrogen antagonist in breast tissue but an agonist
response. These antagonists block the receptor, prevent- in bone tissue; it is a selective estrogen receptor modulator,
ing the binding of natural estrogen. Estrogen antago- or SERM. This “tamoxifen paradox” may be partially
nists oppose the biological actions of estrogen and are explained by the discovery of a second estrogen recep-
therefore also called antiestrogens. Synthetic analogs of tor, ER-beta, which appears to have a different tissue dis-
other reproductive hormones have also been produced tribution than the original receptor, renamed ER-alpha.
(See Box 1.1). (The more abundant ER-alpha is usually referred to as

BOX 1.1

GnRH MIMICS AND BLOCKERS

Gonadotropin-releasing hormone (GnRH), released Some GnRH analogs have been found to inhibit go-
from the hypothalamus of the brain, is the master hor- nadotropin secretion by binding to GnRH receptors on
mone that regulates secretion of a suite of other hormones FSH- and LH-secreting pituitary cells, but not stimulating
essential for reproduction. Once GnRH was discovered, gonadotropin secretion. They occupy the receptors and
one of the first ideas was to give it to men and women block natural GnRH from binding; these molecules that
to treat certain kinds of infertility resulting from hypotha- prevent the action of GnRH are called GnRH antagonists.
lamic dysfunction. For example, women who are deficient They are like a rusty key stuck in a lock, which will not
in GnRH release have gonadotropin levels that are too low open the door and will not permit the use of a good key
to cause ovulation. to do so.
In an attempt to find the most effective type of synthetic The GnRH inhibitory agonists and GnRH antagonists
GnRH, many molecules similar but not identical to GnRH are medically useful for their ability to shut down gonad-
were manufactured. These are termed GnRH analogs. The otropins and, consequently, lower gonadal steroids and
GnRH analogs that stimulate gonadotropin secretion are inhibit egg and sperm maturation. Typically, these drugs
called GnRH agonists (an agonist is a substance that mimics are given as daily or monthly injections, an implant, or
the action of the naturally occurring hormone). Attempts a nasal spray. They are employed to treat endometriosis
to treat infertile patients with injections of GnRH agonists and uterine fibroids by reducing circulating estrogen lev-
resulted in an initial promising surge in FSH and LH lev- els, causing the affected tissues to shrink. They are also
els. But to everyone’s surprise, most of the GnRH agonists being studied as potential contraceptives. In fertility clin-
stopped working after about 10 days because they reduced ics, inhibitory GnRH analogs are used to prevent prema-
the number of GnRH receptors on FSH- and LH-secreting ture ovulation so its timing can be controlled by the use
cells in the pituitary gland. These so-called agonists, when of fertility drugs in in vitro fertilization and gamete in-
given to a person for several days, become GnRH inhibi- trafallopian transfer procedures (see Chapter 15). Despite
tory agonists, a contradiction in terms if there ever was one! their utility, these GnRH agonists often have side effects,
It was discovered that GnRH treatments work only when including menopausal-like symptoms (hot flashes, insom-
the hormone is administered in pulses about 90 min apart, nia, vaginal dryness), osteoporosis, and headaches, and
mimicking the natural secretion pattern of GnRH. Using a they can increase the risk of ovarian cysts. The dramatic
small pump placed under the skin of the abdomen or the effects of these molecules in both promoting and suppress-
arm, pulses of synthetic GnRH can stimulate FSH and LH ing fertility illustrate the central, essential role of GnRH in
secretion and restore fertility in some cases. reproduction.

(Continued)

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

10 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

BOX 1.1 (cont’d)

GnRH
GnRH receptor

Natural
GnRH ↑ FSH, LH =
gain of fertility
Pituitary
cell

Pulsatile
GnRH administration
↑ FSH, LH =
stimulatory gain of fertility
agonist

Loss of
receptors
Constant
administration
GnRH
↓ FSH, LH =
inhibitory
loss of fertility
agonist

GnRH
GnRH
GnRH receptor
blocked
GnRH
↓ FSH, LH =
antagonist
loss of fertility

The effects of various GnRH analogs.

When GnRH (blue ligand) binds to its cell surface receptors on pituitary cells, the cellular response is increased secretion of gonado-
tropins. A synthetic GnRH analog binds to the receptor and acts as a stimulatory agonist (green ligand) when administered in pulses.
However, when administered continuously, a GnRH agonist (red ligand) can actually act as an inhibitory agonist, thus reducing gonado-
tropin secretion. A GnRH antagonist (yellow ligand) occupies the GnRH receptor without eliciting a cellular response, thus blocking the
action of natural GnRH.

“the estrogen receptor.”) The possibility of developing the pituitary gland or hypophysis (Figure 1.9). This gland
pharmaceuticals that mimic a hormone’s effects in some synthesizes and secretes hormones that travel in the blood-
tissues, but block them in others, paves the way for so- stream and influence many aspects of our body, including
called “designer drugs.” the function of other endocrine glands. For example, if the
hypophysis is removed (an operation called hypophysec-
tomy), our reproductive system becomes nonfunctional,
and even sexual behavior is affected. Therefore, this gland
HOW THE BRAIN AND PITUITARY
plays a very important role in our reproductive biology. A
CONTROL REPRODUCTION
realization of the importance of the hypophysis led early
endocrinologists to call it the “master gland.” We now
The Pituitary Gland
know that the activity of this gland, which is connected to
The sphenoid bone lies at the base of your skull, and the base of the brain by a stalk, is itself greatly influenced
in this bone is a small, cup-shaped depression called the by brain messages. Indeed, one might think of the brain as
sella turcica (“Turkish saddle”). Lying in this depression is a the conductor of a marvelous chemical symphony played
round ball of tissue, about 1.3 cm (0.5 in) in diameter, called by the pituitary orchestra.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 How the Brain and Pituitary Control Reproduction 11

Cerebrum

Thalamus
Pineal Hypothalamus
gland

Infundibulum
Pituitary gland
Midbrain
Pons Brain
Medulla stem
Cerebellum oblongata

Spinal cord

FIGURE 1.9 Section through the middle of the brain showing the pituitary gland, hypothalamus, and pineal gland. Note that the pituitary
gland (hypophysis) rests in a depression in the sphenoid bone and is connected to the hypothalamus by the pituitary stalk.

Hypothalamo–Neurohypophysial Connection
travels across the synapse and initiates electrochemical
The hypophysis has two major regions (Figure 1.10). changes leading to nerve impulses in the next neuron.
One is called the adenohypophysis, which is discussed The other general kind of nerve cell is the neurose-
later in this chapter. The other is the neurohypophysis (pars cretory neuron (Figure 1.11). A neurosecretory neuron
nervosa, or posterior pituitary gland). The neurohypophy- is similar to a regular neuron in that it can conduct a
sis is an extension of the brain; it develops as an out- nerve impulse along its axon. The speed of this electrical
growth of the portion of the embryonic brain that later conduction is, however, much slower than in a regular
becomes the hypothalamus. To understand the function neuron. Also, neurosecretory neurons are specialized to
of the neurohypophysis, you must first know that there synthesize large amounts of neurohormones in their cell
are two general types of nerve cells in the body. bodies. These neurohormones are then packaged into
Most of the nerve cells, or neurons, in our nervous sys- large granules that travel in the cytoplasm down the
tem consist of a cell body (containing the nucleus) along axon, and contents of the granules are released into the
with extensions of the cell called dendrites and axons spaces adjacent to the axon ending. The neurohypophy-
(Figure 1.11). Dendrites conduct a nerve impulse toward sis contains long axons of neurosecretory neurons sur-
the cell body, which is usually in or near the central ner- rounded by supporting cells. The cell bodies of these
vous system (brain and spinal cord). A sensory nerve is axons lie in the part of the brain called the hypothalamus.
really a collection of long dendrites carrying messages The hypothalamus forms the floor and lower walls of
to the central nervous system from the periphery. Axons the brain (see Figure 1.9) and contains a fluid-filled cav-
carry information away from the cell body. Motor nerves ity, the third ventricle. This ventricle is continuous with
contain axons that stimulate a response in the body, such the other ventricles in the brain and also with the central
as muscle contraction or glandular secretion. When one canal of the spinal cord. The fluid in the ventricles and
neuron connects with another, information is passed from central canal is called cerebrospinal fluid. The weight of
the first to the second cell; this site of communication is the hypothalamus is only 3 percent of that of the whole
known as a synapse. The axonal ending of the first neu- brain, but it functions in a wide variety of physiological
ron secretes a chemical called a neurotransmitter, which and behavioral activities. For example, there are areas

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

12 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

Hypothalamus milk is ejected from the nipples (see Chapter 12). Also,
oxytocin causes the smooth muscle of the uterus to
contract, and thus it plays a role in labor and child-
birth (see Chapter 11). In the male reproductive tract,
oxytocin may facilitate sperm transport. Vasopressin
causes the kidneys to retain water, i.e., the amount
of urine formed in the kidneys is reduced and more
Optic chiasma water remains in the body. Vasopressin also causes
Median blood vessels to constrict and blood pressure to rise.
Pars tuberalis eminence When oxytocin and vasopressin are released from the
axons in the neurohypophysis, these neurohormones
Pars intermedia
enter small blood vessels (capillaries) in the neurohy-
Pituitary pophysis that drain into larger veins and then enter the
stalk
general circulation.

Adenohypophysis
The adenohypophysis (adeno, meaning “glandular”)
consists of three regions: the pars distalis, the pars inter-
media, and the pars tuberalis (Figure 1.10). The pars
distalis (or anterior pituitary gland) occupies the major
portion (70%) of the adenohypophysis. The pars interme-
dia is a thin band of cells between the pars distalis and
Pars distalis Pars nervosa the neurohypophysis. In the adult human, the pars inter-
media is sparse or absent. The pars tuberalis is a group
FIGURE 1.10 Major subdivisions of the human hypophysis (the
neurohypophysis and the adenohypophysis) and their relationship to
of cells surrounding the pituitary stalk. During embry-
the brain. The pars tuberalis, pars distalis, and pars intermedia are all onic development, the adenohypophysis forms from an
part of the adenohypophysis. In adult humans, the pars intermedia is invagination (inpocketing) of the cell layer of the embryo
often absent. that later becomes the roof of the mouth. This invagina-
OC, optic chiasma (nerves from the eyes). Anterior is to the left. tion of cells then extends toward the neurohypophysis
growing from the embryonic brain.
The adenohypophysis contains several types of endo-
in the hypothalamus that regulate body temperature, crine cells. When we stain the adenohypophysis with
thirst, hunger, sleep, response to stress, and aggressive laboratory dyes, some cells acquire a pink color. These
and sexual behaviors. cells are called acidophils (phil, meaning “love”) because
Of importance to our discussion of the hypophysis is they have an affinity for acid dyes. Some acidophils syn-
that the cell bodies of the neurosecretory axons in the thesize and secrete growth hormone (GH). This hormone
neurohypophysis lie in paired groups (neurosecretory is a large protein that stimulates tissue growth by caus-
nuclei) in the hypothalamus. More specifically, these are ing incorporation of amino acids into proteins. The other
the supraoptic and paraventricular nuclei. (Note: a neuro- type of acidophil in the adenohypophysis synthesizes
secretory nucleus is a group of cell bodies of neurosecre- and secretes prolactin (PRL), which is also a large pro-
tory neurons and should not be confused with “nucleus” tein. As we shall see in Chapter 10, prolactin acts with
as meaning the body within a cell that contains DNA.) other hormones to cause the female mammary glands to
The axons of the neurosecretory neurons in these nuclei become functional and secrete milk.
then pass down the pituitary stalk (which connects the Other cells in the adenohypophysis, the basophils,
hypophysis with the brain) and into the pars nervosa stain darkly with basic dyes. These cells synthesize
of the neurohypophysis (Figure 1.12). The granules and secrete hormones that are proteins or glycopro-
released by these axons contain two neurohormones— teins (large proteins with attached sugar molecules).
oxytocin and vasopressin (or antidiuretic hormone). One of these hormones is the glycoprotein thyrotro-
Both oxytocin and vasopressin are polypeptides pin. The abbreviation for thyrotropin (TSH) comes
consisting of nine amino acids. The two neurohor- from the older name, thyroid-stimulating hormone.
mones differ only slightly in the kinds of amino acids This hormone causes the thyroid glands to synthesize
in their molecules, but these slight differences result in and secrete thyroid hormones (e.g. thyroxine), which
very different effects on our bodies. Oxytocin stimu- in turn control the rate at which our tissues use oxy-
lates contractile cells of the mammary glands, so that gen. Other basophils in the adenohypophysis secrete

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 How the Brain and Pituitary Control Reproduction 13

(A) (B)

Dendrite

Cell body

Axon

Neurotransmitters Neurohormones
FIGURE 1.11 A regular neuron (A) and a neurosecretory neuron (B). Dendrites carry nerve impulses toward the cell body, whereas axons
carry nerve impulses away from the cell body. Neurotransmitters are secreted by the axon endings of regular neurons, whereas neurohormones
(dark dots in B) are released from the axon endings of neurosecretory neurons.

Paraventricular
nucleus corticotropin (ACTH), a polypeptide hormone that
travels in the blood to the adrenal glands and causes
Ventricle III
secretion of adrenal steroid hormones (corticosteroids)
Hypothalamus such as cortisol. Cortisol in turn raises blood sugar
Hypophysiotropic
area levels, reduces inflammation, and combats the effects
Supraoptic Median eminence of stress. Still other basophils in the adenohypophy-
nucleus
Neurosecretory neurons of sis secrete the polypeptide hormones lipotropin (LPH)
Pars HTA secrete releasing and melanophore-stimulating hormone (MSH). Lipotro-
distalis hormones or pin breaks down fat to fatty acids and glycerol. MSH
release-inhibiting hormones
into the median eminence. causes synthesis of a brown pigment, melanin, which
These neurohormones reach is present in cells called melanophores. Finally, the
the pars distalis via the basophils of the adenohypophysis secrete two kinds
hypothalamo-hypophysial
portal system. of natural, opioid-like “pain-killers”—the endorphins
and enkephalins.
Of particular interest to our discussion of human
Neurosecretory axons from
the supraoptic and reproductive biology are the final two hormones
paraventricular nuclei secrete secreted by basophils of the pars distalis. One of these
Pars nervosa oxytocin and vasopressin. is follicle-stimulating hormone (FSH). We shall learn in
FIGURE 1.12 Regions of the hypothalamus involved in the func- Chapter 4 that FSH plays a role in sperm production in
tion of the hypophysis. the testes. In the female, FSH stimulates the ovaries to

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

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14 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

produce mature germ cells in their enclosed tissue sacs been observed that menstrual cycles of women are often
(see Chapter 2). The other hormone is luteinizing hor- altered or even stopped by stressful environmental and
mone (LH), which causes interstitial cells in the testes psychological stimuli (see Chapter 3). This pointed to an
to synthesize and secrete androgens (see Chapter 4). In influence of the brain on reproductive physiology. It was
the female, LH causes the ovaries to secrete female sex not until 1947, however, that J. D. Green and G. W. Harris
hormones (estrogens and progestins) and induces the provided anatomical evidence that neurosecretory
release of an egg from the ovary (see Chapter 2). Because ­neurons in the hypothalamus could influence the func-
FSH and LH play vital roles in the function of the gonads, tion of the adenohypophysis. Recall that some of the
they are grouped under the term gonadotropic hormones neurosecretory neurons in the hypothalamus send their
or “gonadotropins.” The pituitary cells that release axons down the pituitary stalk and into the neurohy-
gonadotropins are termed gonadotropes. These cells are pophysis, where they release oxytocin and vasopressin.
scattered throughout the pars distalis and comprise Other neurosecretory neurons existing in paired nuclei
7–15% of cells in the anterior pituitary. Although most in the hypothalamus do not send their axons down the
gonadotropes contain both FSH and LH, some stain for stalk to the pituitary. Instead, their axons end in an area
only one of the gonadotropins. Thus, gonadotropes may in the floor of the hypothalamus near the pituitary stalk,
be a heterogeneous population of cells that differentially called the median eminence. (Note: sometimes the median
synthesize and release FSH and/or LH depending on eminence is considered part of the neurohypophysis.)
physiological state, maturity of the cell, or other condi- The cell bodies of these neurons are clustered in sev-
tions. Figure 1.13 summarizes the hormones secreted by eral pairs of nuclei in the hypothalamus, and together
the pituitary gland. these nuclei are named the hypophysiotropic area (HTA,
Figure 1.12). These nuclei are given this name because
the neurosecretory neurons in this region secrete a fam-
Hypothalamo–Adenohypophysial Connection ily of small polypeptides (neurohormones) that either
It has been known for some time that the reproduc- increase or decrease the amount of hormones secreted
tive cycles of many animals are influenced by such envi- by the adenohypophysis.
ronmental factors as light, behavior, and stress, and the If the neurohormones controlling adenohypophysial
same appears true for humans. For example, it had long function are released from neurosecretory neurons at the

Hypothalamus

Pars distalis of adenohypophysis

Neurohypophysis
Opioids
Vasopressin GH
Oxytocin LPH
ACTH
MSH

PRL

LH

FSH
TSH Adrenal
cortex

Pigment Fat cells

cells

Mammary Ovaries Thyroid Kidney

glands Testes

Pain
Progesterone, estrogens Testosterone Thyroxine Corticosteroids Growth Nerves

FIGURE 1.13 The pituitary, connected to the hypothalamus at the base of the brain, has two lobes. The neurohypophysis stores and releases
two hormones made in the hypothalamus: oxytocin and vasopressin. Oxytocin causes contraction of smooth muscle in the uterus, breast, and
male reproductive tract. Vasopressin acts on the kidneys to cause water retention. The adenohypophysis secretes nine other hormones: growth
hormone (GH) promotes growth; corticotropin (ACTH) causes the adrenal cortex to secrete corticosteroid hormones; follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) interact to regulate the function of the gonads; prolactin (PRL) causes milk synthesis in the mammary glands;
thyrotropic hormone (TSH) stimulates the thyroid gland to secrete thyroxine; lipotropin (LPH) affects fat metabolism; melanophore-stimulating
hormone (MSH) stimulates melanin synthesis in pigment cells; and opioids (endorphins and enkephalins) reduce pain.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 How the Brain and Pituitary Control Reproduction 15
median eminence, how do they reach the adenohypoph- Primary capillary plexus
ysis to influence pituitary hormone secretion? In 1930, of median eminence
Hypothalamus
G. T. Popa and U. Fielding described a specialized system
of blood vessels extending from the median eminence
to the pars distalis (Figure 1.14). The superior hypophy-
sial arteries carry blood to the median eminence region. Internal
These arteries drain into a cluster of capillaries in the carotid
median eminence known as the primary capillary plexus. artery
Hypophysial
The neurohormones diffuse into these capillaries and Superior portal veins
into the blood. Then they are carried down to the pars hypophysial
Capillaries in
arteries
distalis in small veins. These veins divide into a second neurohypophysis
capillary bed surrounding the cells of the pars distalis, Secondary
capillary plexus Inferior
the secondary capillary plexus. The neurohormones then hypophysial
in pars distalis
leave the blood through the walls of these capillaries and artery
Inferior
enter the spaces between the pars distalis cells, where hypophysial vein Internal
they cause these cells to either increase or decrease carotid
hormone synthesis and secretion. This efficient system artery
Inferior
allows, for example, a very small amount of the neuro- Cavernous hypophysial
hormone gonadotropin-releasing hormone (GnRH), undi- sinus vein
luted by the general circulation, to be delivered directly FIGURE 1.14 The hypothalamo–hypophysial vascular system.
to its target—gonadotropes in the pituitary—and pre- Arterial blood enters the median eminence and the neurohypophysis
cisely influence their activity. via the superior hypophysial and inferior hypophysial arteries, re-
A portal system is a vascular arrangement in which spectively. Both of these arteries are branches of the internal carotid
blood flows from one capillary bed to another with- arteries, major vessels supplying the brain. Neurohormones secreted
into the median eminence region enter the blood in the primary capil-
out going through the heart. Thus, the vascular system lary plexus. They pass down the hypophysial portal veins to the sec-
connecting the median eminence with the pars distalis ondary capillary plexus in the pars distalis. Then they leave the blood
is called the hypothalamo–hypophysial portal system, and and cause the pars distalis cells to secrete or stop secreting hormones.
the small veins connecting the primary and secondary When hormones are secreted by the pars distalis, they leave the hy-
capillary plexi are the hypophysial portal veins. Once the pophysis in the inferior hypophysial veins, which drain into a large
vessel, the cavernous sinus. Neurohypophysial hormones enter cap-
hormones of the adenohypophysis are secreted, they illaries in the neurohypophysis, which also drain into the cavernous
leave the pituitary via the inferior hypophysial vein sinus. Small blood vessels connect the capillaries of the pars distalis
(Figure 1.14). and neurohypophysis.

Releasing and Release-Inhibiting Hormones TABLE 1.1 Hypothalamic Neurohormones Controlling the
Synthesis and Release of Hormones from the Pars Distalis
The neurohormones released by the axons of the
Neurohormone Abbreviation
hypophysiotropic area of the hypothalamus can either
increase or decrease the synthesis and secretion of hor- Gonadotropin-releasing hormone GnRH
mones of the adenohypophysis. When a neurohormone
Prolactin release-inhibiting PRIH
increases output of a particular adenohypophysial hor- hormone (dopamine)
mone, it is called a releasing hormone (RH). For example,
Corticotropin-releasing hormone CRH
the neurohormone that increases the output of thyrotro-
pin is called thyrotropin-releasing hormone (TRH). When a Thyrotropin-releasing hormone TRH
neurohormone lowers the secretion of a particular ade- Growth hormone-releasing hormone GHRH
nohypophysial hormone, it is termed a release-inhibiting
Growth hormone release-inhibiting GHRIH
hormone (RIH). Thus, the neurohormone that decreases
hormone (or somatostatin)
the secretion of prolactin is prolactin release-inhibiting hor-
mone (PRIH). Those of particular interest to reproductive biologists are in bold.
As seen in Table 1.1, most hormones of the adeno-
hypophysis are controlled by a releasing hormone, these neurohormones are known. The others are rec-
and some are known to be controlled by both a releas- ognized as a result of experiments demonstrating their
ing and a release-inhibiting hormone. Each releasing or presence, but their chemical nature is yet to be described.
release-inhibiting hormone is probably synthesized by a In 1977, Andrew Schally and Roger Guillemin shared the
different group of neurosecretory cell bodies in the hypo- Nobel Prize in Physiology or Medicine for their research
physiotropic area. The chemical structures of several of on hypothalamic neurohormones.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

16 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

Of particular interest to us are the neurohormones GnRH is actually derived within the neuron from
that control synthesis and release of FSH, LH, and PRL a larger protein called prepro-GnRH (Figure 1.16). This
from the pars distalis. We shall discuss these in some protein contains the 10 amino acids of GnRH, plus a
detail because research about these neurohormones has “signal sequence” of 23 amino acids (which plays a
had a profound influence in controlling human fertility role in breaking up prepro-GnRH into its component
and treating reproductive disorders. parts), a sequence of three amino acids used for molec-
ular processing, and a 56-amino acid sequence called
GnRH-associated peptide (GAP). Before secretion of
Gonadotropin-Releasing Hormone GnRH, the prepro-GnRH molecule is split into GnRH
Evidence that a substance released by the hypothalamus and GAP.
controls pituitary LH secretion was confirmed in the early
1970s when luteinizing hormone-releasing hormone (LH-RH)
The GnRH Pulse Generator and Surge Center
was isolated and its chemical nature identified, primarily
through the efforts of Andrew Schally. Many thousands of GnRH is not released continuously from the hypothal-
hypothalami from domestic mammals were obtained to amus. Instead, it is secreted in pulses every hour or so into
extract and purify this neurohormone. LH-RH is a polypep- the hypophyseal portal system. In response, the pituitary
tide, consisting of 10 amino acids, and its function has been gonadotropes release FSH and LH in a pulsatile fashion.
examined in a wide variety of research and clinical studies. The pulsatile pattern of GnRH secretion is essential for
Surprisingly, when LH-RH is administered to humans or to gonadotropin secretion, and thus is central to reproduc-
laboratory mammals, both LH (Figure 1.15) and, to a lesser tive function. This is demonstrated in the treatment of
degree, FSH are secreted in increased amounts into the men and women whose infertility is caused by insuf-
blood. Therefore Schally concluded that there may be only ficient gonadotropin levels. Initially, it was thought that
one releasing hormone in humans that controls synthesis simply giving the patients GnRH agonists would restore
and secretion of both LH and FSH. This is despite evidence fertility. Surprisingly, after initial stimulation of FSH and
that the hypothalamus of some mammals contains LH-RH LH, these agonists stopped working. Only when GnRH
as well as a follicle-stimulating hormone-releasing hormone agonists are administered in natural pulses by an intra-
(FSH-RH) that causes release of mostly FSH and a little venous pump is normal gonadotropin secretion restored.
LH. Although future research may show that the human It is thought that continuous exposure to GnRH down-
hypothalamus secretes both LH-RH and FSH-RH, let us regulates its receptors or the GnRH signaling pathway in
for now accept that a single releasing hormone increases pituitary cells.
both LH and FSH secretion from the pituitary; we call this In humans, the GnRH-secreting cells are mainly
gonadotropin-releasing hormone (GnRH), realizing that this located in a part of the HTA called the arcuate nucleus,
is identical to the LH-RH discussed in the older scientific though others are scattered elsewhere in the hypothala-
literature. About 1000 to 3000 neurons in the HTA secrete mus. This nucleus is at the base of the hypothalamus
GnRH (see Box 1.2). Many of these neurons send their near the median eminence; it also contains regular neu-
axons to the median eminence to exert control over pitu- rons that synapse with the GnRH neurons. Pulsatile
itary LH and FSH secretion. Some GnRH neurons, how- secretion of GnRH is controlled by activity of cells in
ever, send axons to other brain regions and may influence this region, known as the GnRH pulse generator. Pulsa-
sexual behavior. tile release of GnRH is an intrinsic property of GnRH
neurons, and the frequency and amplitude of these
pulses may be influenced by synapses with regular
25
neurons as well. Neurons in the hypothalamus modify
21 GnRH secretion through several neurotransmitters.
17 Kisspeptins, a family of peptides released by neurons in
LH (ml U/ml)

Women
13

9
Men Signal GnRH-associated
5 polypeptide GnRH peptide (GAP)

1
–5 0 8 16 32 64 128 10 amino
23 amino acids 3 aa 56 amino acids
Time (min) acids

FIGURE 1.15 When a single injection of GnRH is administered to Prepro-GnRH

men (▲) and women (●) at time zero, levels of LH rise in the blood,
peak after 32 min, and then decline. Levels of FSH (not shown) also rise FIGURE 1.16 Components of prepro-GnRH, the large protein that
after GnRH administration, but not as high as LH. gives rise to GnRH and GAP.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 Feedback Control of Gonadotropin Secretion 17
close anatomical association with GnRH cells, appear to
act directly on GnRH neurons to stimulate GnRH secre-
Pineal Gland
tion (Figure 1.17). In addition, norepinephrine, dopamine, The pineal gland, a single outpocketing from the roof
gamma-aminobutyric acid (GABA), glutamate, and even of the brain (see Figure 1.1), may also influence the
GnRH itself (acting through autocrine signaling) have release of FSH and LH. In the seventeenth century, it
been proposed as GnRH regulators. Another neuropep- was believed that this gland was the “seat of the soul.”
tide, gonadotropin-inhibitory hormone (GnIH), nega- Now we know that the pineal synthesizes and secretes
tively regulates GnRH by inhibiting GnRH cell function the hormone melatonin, which can inhibit the reproduc-
and gonadotrope response to GnRH in mammals, tive systems of male and female mammals. Exposure of
though its exact function in humans is not yet known. humans to light suppresses melatonin secretion, whereas
Thus, GnRH secretion can be stimulated or inhibited by exposure to dark increases it. Light does not directly
a complex pattern of neuronal activity in the brain. affect the pineal. Instead, light entering the eyes increases
At mid-cycle in females, GnRH-secreting cells release activity of nerves in the accessory optic tracts leading to
even more GnRH, resulting in a surge of FSH and LH the brain. These impulses cause the part of the sympa-
from the pituitary. The GnRH surge center activity con- thetic nervous system that innervates the pineal gland to
trolling this event also resides in the hypothalamus. The decrease release of the neurotransmitter norepinephrine.
importance of the GnRH pulse generator and surge cen- This then causes a decrease in melatonin synthesis and
ter in the control of the menstrual cycle is discussed in secretion. Because of this influence of the daily light cycle
Chapter 3. on melatonin secretion, levels of melatonin in the blood
exhibit a daily cycle. In humans, plasma melatonin levels
are highest during sleep, between 11 pm and 7 am. When
the daily light schedule is shifted by 12 h, it takes four
KISS or five days for the daily rhythm in melatonin to shift
Neuron
to the new light cycle. In addition to daily light cycles,
+ sleep and activity patterns can also influence melatonin
+ cycles in humans. Conversely, melatonin levels can affect
sleep–wake and other circadian rhythms. Melatonin may
– play a role in normal puberty (see Chapter 6), as levels of
GnRH this hormone in the blood of prepubertal children drop
Neuron markedly just before the onset of puberty.
We have much more to learn about the role of the
pineal in reproduction. Analogs of melatonin have been
made in the laboratory and found to inhibit the human
reproductive system when given orally. These analogs
GnRH could act on the hypothalamus, pituitary gland, or
gonads to inhibit reproduction. Considering this hor-
Estradiol + mone’s potential impact on reproduction, it is surprising
that melatonin pills are being sold over the counter in
the United States with little control over dosage or con-
sideration of side effects.
Pituitary

FEEDBACK CONTROL OF
FSH
GONADOTROPIN SECRETION
Ovary LH
+ Feedback Systems
FIGURE 1.17 Proposed mediation of estradiol feedback in women. In your house or apartment, you probably have a
In response to GnRH, the pituitary releases LH, which is trans- thermostat on your wall that controls the activity of
ported to the ovaries. Estradiol, secreted by the ovaries, then feeds your heating system, and you can set the temperature
back on GnRH. Because GnRH neurons lack estrogen receptors, of your room by manipulating a dial on the thermostat.
both positive and negative feedback is thought to be mediated by Now, suppose you set the thermostat at 65 °F. This tem-
other neurons in the hypothalamus. Kisspeptin-secreting neurons
are good candidates, as they are responsive to estradiol, synapse
perature is called the “set point.” The thermostat con-
with GnRH neurons, and release kisspeptins that stimulate GnRH tains a small strip, made of two metals, that expands
neuron activity. or contracts depending on the temperature. If the room

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

18 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

BOX 1.2

KALLMANN SYNDROME AND THE ORIGIN AND

M I G R AT I O N O F G n R H C E L L S
Kallmann syndrome is one of the many possible causes (sex linked) or are autosomal, and it is five to seven
of human infertility (see Chapter 15). People with this times more common in men (see Chapter 5). About
syndrome exhibit a curious association of infertility one in 10,000 men are born with this condition. Fer-
with anosmia (the inability to smell). ­ Examination tility of Kallmann syndrome sufferers can be restored
of their nervous system has revealed an absence of with the administration of GnRH stimulatory ago-
­certain olfactory (smell) structures in the brain as well nists, but they would still remain anosmic for life.
as a lack of GnRH neurons in the hypothalamus; the What is the explanation for the association of
latter deficiency accounts for their low secretion of ­olfactory and reproductive abnormalities in people
­gonadotropins (FSH and LH) and infertility. with this syndrome? During normal embryonic de-
velopment, the olfactory nerves carry neural infor-
Developing
brain
mation from the olfactory lining in the nasal cavity to
the pair of olfactory bulbs at the base of the cerebral
hemispheres of the brain. From there, the olfactory
sense is carried in nerve fibers of the olfactory tracts
to the hypothalamus and other brain areas. Once the
olfactory system is formed in the embryo (at about
LV day 25 of pregnancy), GnRH cells, which originate in
F the developing nasal cavity (nose), migrate along the
olfactory nerves and tracts to the hypothalamus, where
ON
they take up residence in the arcuate nucleus and pre-
pare to play a role in controlling pituitary FSH and
A LH secretion and reproduction in the adult. People
with ­Kallmann syndrome, however, do not develop a
OL normal olfactory system, so the GnRH cells have no
“olfactory highway” of nerve fibers to guide them on
   their journey to the hypothalamus. Thus, the GnRH
Diagram of a section through the head of a human embryo show- cells of people with Kallmann syndrome remain
ing the migration route of GnRH neurons (green dots) from the stuck in the nose! Why is development of the GnRH
nasal cavity to the hypothalamus. Failure to migrate, as in Kall- neurons so interwoven with that of the olfactory sys-
mann syndrome, results in GnRH cells remaining in the nose and tem? Chapter 8 discusses the important role of social
in infertility. A, arcuate nucleus of the hypothalamus (GnRH cells
migrating to here control gonadotropin secretion in the adult); F,
chemical signals (“pheromones”) in the reproduction
forebrain (route of migration in brain); LV, lateral ventricle; OL, of mammals, including perhaps humans. The intimate
olfactory lining in developing nasal cavity; ON, olfactory nerve association of the development of GnRH cells with
fibers (route of migration outside brain); large arrows, migration the olfactory system may have evolved because of the
pathways of GnRH cells. Adapted from Schwanzel-Fukuda et al. importance of linking sensory chemical information
(1992).
from the opposite sex to gonadotropin secretion and
Kallmann syndrome is inherited; genes associated
fertility.
with this disorder are located on the X chromosome

temperature drops below 65 °F, the thermostat sends an information into a message (“input”). In your thermo-
electrical current through the wires leading to the heater, stat, the input travels along wires from the temperature
and the heater is activated. When the room temperature receptor (bimetal strip) and then to a “controller center.”
reaches 65 °F, the heater shuts off. Thus, the product of The controller center contains the set point and also gen-
the heater (heat) influences the activity of the heater by erates an outgoing message (“output”). Wires leading
feeding back on the device in the thermostat that con- from the controller center in the thermostat to the heater
trols the heater activity. carry this output message. These output wires are acti-
A simple feedback system is depicted in Figure 1.18. A vated when the room temperature is below the set point.
receptor detects changes in the system and translates this The “effector” (heater) then responds by producing an

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 Feedback Control of Gonadotropin Secretion 19

Regular neurons

Arcuate nucleus of hypothalamus

Higher
center

Input Controller Output Feedback

center effects of
(set point) gonadal
hormones Blood
GnRH
Effector cell
Receptor

Feedback loop Change Gonadal

eminence
in system Effect hormones Gonads

Median
GnRH (ovaries
FIGURE 1.18 A simple feedback system. The receptor detects the or testes)
level of a particular component of the system and translates it into a FSH, LH
message (input) to the controller center. The input is compared by the

Pituitary
controller center to its programmed set point, and this center computes Portal

stalk
whether a regulatory response is required. If necessary, the controller veins
center generates a signal (output) that is transmitted to one or more
effectors, which respond by producing some effect. This effect produces
a change in the system, which then feeds back as a feedback loop on

(pars distalis)
Hypophysis
the controller center after being received by the receptor. Other circuits GnRH
(higher centers) can modify the activities of the controller center by Blood
temporarily altering the set point or by inhibiting the operation of the FSH LH
controller center. cell cell
FSH LH
“effect” (heat). In turn, the effect produces a change in
the system (an increase in room temperature) that has
a feedback effect on the controller center. This is called FIGURE 1.19 Schematic diagram of the control of the reproductive
system by the brain and pituitary gland and the sites of feedback by
a feedback loop. In some feedback systems, other circuits
gonadal hormones on this control.
(“higher centers” in Figure 1.18) can modify the activi-
ties of the controller center by temporarily altering the
set point or by inhibiting the operation of the controller by having feedback effects on the systems controlling
center. gonadotropin secretion.
Many aspects of our physiology operate as feedback In women, moderate plasma levels of estrogen reduce
systems that regulate our internal environment at a the secretion of FSH and LH from the pituitary. This nega-
steady state; this regulation is called homeostasis. Homeo- tive feedback effect of estrogen (Figure 1.19) is even more
static control systems in our body operate through nega- effective in combination with high levels of a progestin.
tive feedback. In the endocrine system, negative feedback In the normal menstrual cycle, high levels of progester-
occurs when the plasma level of a hormone rising above one and moderate levels of estrogens in the blood during
a set point inhibits further secretion of that same hor- the luteal phase of the cycle (the period between ovula-
mone into the blood. In reproductive physiology, there tion and menstruation) lower gonadotropin secretion by
are also important occurrences of positive feedback, in negative feedback and thus prevent ovulation at this time
which the secretion of a hormone influences the control- (see Chapter 3). Similarly, combination contraceptive pills
ler center so secretion of that hormone increases even containing moderate levels of an estrogen and high levels
more. Both positive and negative feedback are impor- of a progestin are highly effective at inhibiting gonado-
tant in controlling secretion of the gonadotropins from tropin secretion and thus ovulation (see Chapter 13).
the adenohypophysis. It may help you to think that the hypothalamus con-
tains a controller center with a gonadostat that works like
the thermostat in your heating system. This gonadostat
Regulation of Gonadotropin Secretion by
contains a set point for levels of sex steroids (estrogens,
Negative Feedback progestins, or androgens) in the bloodstream. When
As discussed in Chapters 2–4, FSH and LH cause levels of these steroids are higher than the set point, the
secretion of sex hormones by the gonads (testes or ova- gonadostat signals the hypophysiotropic area to stop
ries). These steroid hormones (androgens, estrogens, secreting GnRH, and thus secretion of FSH and LH from
and progestins) are products (effects) of the action of the adenohypophysis declines. If circulating levels of
gonadotropins on the gonads, and it turns out that ste- steroids are below the set point, the gonadostat signals
roid hormones influence the secretion of LH and FSH the hypophysiotropic area to release more GnRH, and

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

20 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

circulating levels of FSH and LH rise. This negative feed- Positive Feedback
back system operates in males and females to maintain
sex steroid levels at a steady state. Thus far, we have been talking about negative feed-
Because GnRH neurosecretory neurons probably do back on pituitary FSH and LH secretion (see Figures
not have receptors for sex steroids, the negative feedback 1.18 and 1.19). There is, however, a stage in the human
effects of these steroid hormones must act on other neu- menstrual cycle when high levels of plasma estrogen
rons in the brain, which in turn inhibit GnRH cells. As increase the secretion of LH and FSH from the adenohy-
mentioned before, GnRH neurons are closely associated pophysis, which in turn further increase estrogen release
with a population of neurons that secrete the protein from the ovary. This temporary escalation of hormone
known as kisspeptin. Kisspeptin-secreting neurons pos- release is an example of positive feedback. It results in
sess receptors for androgens, estrogens, and progestins, a “surge” of gonadotropins (primarily LH) in the blood
and thus these neurons are proposed to be critical play- and the subsequent release of an egg from the ovary
ers in the negative feedback of steroids on the hypothala- (see Chapter 3), ending the positive feedback cycle. It is
mus (Figure 1.17). Some of the negative feedback effects important to understand that the negative and positive
of sex steroids can also act directly on the FSH and LH feedback effects of estrogen have separate and different
pituitary cells by decreasing their sensitivity to GnRH. set points. High levels of estrogen in the blood (above
In addition to secreting steroid hormones in response the positive-feedback set point) have a positive feedback
to FSH and LH, the gonads (testes and ovaries) also effect on gonadotropin secretion, whereas moderate lev-
release glycoprotein hormones that influence gonado- els of estrogen (but still above the set point for negative
tropin secretion. Inhibin, produced by the gonads, enters feedback) have a negative effect on gonadotropin secre-
the circulation and acts directly on pituitary cells to tion (Figure 1.20). The positive feedback effect of high
selectively suppress the secretion of FSH but not LH. levels of estrogen operates by stimulating neural activity
Thus, inhibin acts as a feedback regulator to control FSH in the hypothalamic surge center, which then increases
secretion. Activin opposes the action of inhibin, stimu- GnRH secretion. As with negative feedback, kisspeptin-
lating the release of FSH. Activin is also synthesized in secreting neurons have an important role in mediating
the pituitary, brain, and other tissues, and it may have positive feedback of steroids on the hypothalamus.
local (paracrine) effects as well as behave as a blood- The positive and negative feedback effects of gonadal
borne hormone. Although they exert opposite effects steroids on LH and FSH secretion can operate directly on
on FSH secretion, activin and inhibin are closely related the pituitary itself as well as on the brain (Figure 1.19),
proteins in the transforming growth factor beta (TGF- i.e., the response of FSH- and LH-secreting cells in the
β) superfamily. Both are dimers, or complexes formed adenohypophysis to GnRH may vary depending on the
by the joining of two protein subunits. Activin is made kinds and amounts of steroid hormones bathing these
from two similar or identical beta subunits, whereas cells. For example, it has been shown that high estrogen
inhibin has a beta subunit and an alpha subunit. levels increase the sensitivity of the pituitary to GnRH.
Another glycoprotein that is produced by many cell Progestins can also increase pituitary sensitivity to
types, follistatin, binds to activin and blocks its action. GnRH in women. In males, androgens have a negative
Activin, inhibin, and follistatin are also produced by the feedback on gonadotropin secretion not only by influ-
placenta, and their possible roles in pregnancy are yet encing the brain but also by decreasing the response of
to be discovered. the adenohypophysis to GnRH.

FIGURE 1.20 The actions of positive and negative feedback on GnRH and, therefore, gonadotropin (FSH and LH) and sex steroid secretion
in females and males.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

 Summary 21

Control of Prolactin Secretion receive these hormones, which then travel in the blood
of the hypothalamo–hypophysial portal system to the
The control of PRL secretion by the brain differs in endocrine cells of the adenohypophysis. The releasing
some respects from brain control of LH and FSH secre- hormones then increase the secretion of specific adeno-
tion. If the hypophysiotropic area of the hypothalamus hypophysial hormones, whereas the release-inhibiting
is destroyed, secretion of PRL from the adenohypophy- hormones have the opposite effect.
sis increases, whereas secretion of LH and FSH declines. Because one of these hypothalamic-releasing hor-
Therefore, there is a prolactin release-inhibiting hormone mones increases the secretion of both FSH and LH, it is
(PRIH) secreted by neurosecretory neurons in the hypo- called a gonadotropin-releasing hormone. Because GnRH
physiotropic area that inhibits prolactin secretion. The regulates the release of gonadotropic hormones, which
major PRIH is dopamine; other factors such as GABA themselves control gamete production and hormone
and somatostatin may also play more minor inhibitory release from the gonads (ovaries and testes), GnRH plays
roles. In addition to tonic inhibition by dopamine, PRL a central role in human reproduction. The surge center
may be positively regulated by substances that serve of the hypothalamus causes a surge of LH secretion just
as prolactin releasing factors. Candidates for releas- before ovulation by increasing GnRH secretion from the
ing factors include TRH, which stimulates thyrotropin HTA. The pineal gland secretes the hormone melatonin,
secretion, oxytocin (a posterior pituitary hormone that which exerts inhibitory effects on gonadotropin secretion.
serves reproductive functions), or neurotensin (a neu- Feedback systems control FSH and LH secretion from
ropeptide). Finally, estrogens increase the response of the adenohypophysis. FSH and LH cause the gonads
prolactin-secreting cells in the adenohypophysis to PRH. to secrete gonadal hormones (estrogens, progestins,
Knowledge of the hypothalamic control of prolactin androgens, glycoproteins), that can decrease (by nega-
secretion is important because of this hormone’s role in tive feedback) further secretion of FSH and LH. Estrogen
milk synthesis by the mammary glands (see Chapter 12) also can have a positive feedback effect on LH secre-
and the association of abnormally high levels of PRL tion in women. Prolactin secretion from the pars dista-
with certain kinds of infertility (see Chapter 15). lis is controlled by a prolactin release-inhibiting factor
(dopamine) from the hypothalamus, along with possible
SUMMARY prolactin-releasing factors.

Exocrine glands secrete their products directly into

Further Reading
ducts, whereas endocrine glands release their products
(hormones) into the bloodstream. Specific hormones Adlerkreutz, H., Mazur, W., 1997. Phyto-estrogens and Western diseases.
Ann. Med. 29, 95–120.
influence the growth and function of certain target tis-
Blanco, S.D., Kaiser, U.B., 2009. The genetic and molecular basis of
sues. Hormones can be proteins or smaller polypeptides, idiopathic hypogonadotropic hypogonadism. Nat. Rev. Endocrinol.
amines, steroids, or fatty acid derivatives. Methods used 5, 569–576.
in the science of endocrinology include bioassay, radio- Caprio, M., et al., 2002. Leptin in reproduction. Trends Endocrinol.
immunoassay, nonradioactive methods such as ELISA, Metab. 12, 65–72.
Cullinan, W.E., et al., 2008. Functional role of local GABAergic influ-
and molecular techniques. Paracrines are local chemical
ences on the HPA axis. Brain Struct. Funct. 213, 63–72.
messengers that are not transported in the blood. Edson, M.A., et al., 2009. The mammalian ovary from genesis to revela-
The pituitary (hypophysis) has two major parts: the tion. Endocr. Rev. 30, 624–712.
neurohypophysis and the adenohypophysis. Neurose- Gordon, K., Hodgen, G.D., 1992. Evolving role of gonadotropin-releasing
cretory neurons in the hypothalamus synthesize oxytocin hormone antagonists. Trends Endocrinol. Metab. 3, 259–263.
Guerra, M., et al., 2010. Cell organization of the rat pars tuberalis: evi-
and vasopressin, which travel to the neurohypophysis
dence for open communication between pars tuberalis cells, cere-
in neurosecretory cell axons. The adenohypophysis con- brospinal fluid and tanycytes. Cell Tissue Res. 339, 219–222.
tains three regions: the pars distalis, pars tuberalis, and Kalra, S.P., 1993. Mandatory neuropeptide-steroid signaling for the
pars intermedia (reduced or absent in humans). Cells preovulatory luteinizing hormone-releasing hormone discharge.
in the pars distalis secrete follicle-stimulating hormone, Endocr. Rev. 14, 507–538.
Kaur, K.K., et al., 2012. Kisspeptins in human reproduction—future
luteinizing hormone, prolactin, corticotropin, growth
therapeutic potential. J. Assist. Reprod. Genet. 10, 999–1011.
hormone, thyrotropin, lipotropin, endorphins, and Krsmanovic, L.Z., et al., 2009. The hypothalamic GnRH pulse genera-
enkephalins. Other pituitary cells secrete melanophore- tor: multiple regulatory mechanisms. Trends Endocrinol. Metab.
stimulating hormone, and the pars tuberalis could also 20, 402–408.
secrete FSH and LH. McDonnell, D.P., 1999. The molecular pharmacology of SERMs. Trends
Endocrinol. Metab. 10, 301–311.
Neurosecretory neurons in the hypophysiotropic
Nillsson, S., et al., 1998. ERß: a novel estrogen receptor offers the potential
area of the hypothalamus secrete releasing hormones or for new drug development. Trends Endocrinol. Metab. 9, 387–395.
release-inhibiting hormones into the median eminence Peyeon, C., et al., 2009. Role of melanin-concentrating hormone neuro-
region at the base of the hypothalamus. Here, capillaries peptin in sleep regulation. Peptides 30, 2052–2059.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

22 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND

Roseweir, A.K., Millar, R.P., 2009. The role of kisspeptin in the control Stojilkovic, S.S., et al., 1994. Gonadotropin-releasing hormone neurons:
of gonadotrophin secretion. Hum. Reprod. Update 15, 203–212. intrinsic pulsatility and receptor-mediated regulation. Trends
Rothman, M.S., Wierman, M.E., 2008. Female hypogonadism: evalu- Endocrinol. Metab. 5, 201–209.
ation of the hypothalamus–pituitary–ovarian axis. Pituitary 111, Tena-Sempere, M., 2010. Kisspeptin signalling in the brain: recent devel-
163–169. opments and future challenges. Mol. Cell. Endocrinol. 314, 164–169.
Schwanzel-Fukuda, M., et al., 1992. Biology of luteinizing hormone- Tsusumi, R., Webster, N.J., 2009. GnRH pulsatility: the pituitary re-
releasing hormone neurons during and after their migration from sponse and reproductive dysfunction. Endocr. J. 56, 729–737.
the olfactory placode. Endocr. Rev. 13, 623–634. Tsutsui, K., et al., 2012. Gonadotropin-inhibitory hormone: discovery,
Seminara, S.B., Crowley Jr, W.F., 2008. Kisspeptin and GPR54: discov- progress and prospect. Gen. Comp. Endocrinol. 77, 305–314.
ery of a novel pathway in reproduction. J. Neuroendocrinol. 20, Ubuka, T., et al., 2009. Identification of human GnIH homologs, RFRP-1
727–731. and RFRP-3, and the cognate receptor, GPR147 in the human hypo-
Shaw, N.D., et al., 2009. Aging attenuates the pituitary response to thalamic pituitary axis. PLoS One 4, 1–14.
gonadotropin-releasing hormone. J. Clin. Endocrinol. Metab. 94, Vitzhum, V.J., 2009. The ecology and evolutionary endocrinology of
3259–3264. reproduction in the human female. Am. J. Phys. Anthropol. 140
Skinner, D.C., et al., 2009. Effects of gonadotropin-releasing hormone (Suppl. 49), 95–136.
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I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

Other documents randomly have
different content
stride there was nothing the matter with him. I had not heard from
the horse for nearly a week when one day as the owner was driving
by I hailed him asking how was Rustler, he said “he is all right, there
isn’t a thing the matter with him.” He went to the races, started in at
Baltimore, Maryland, and after winning seven or eight consecutive
races, finished at Readville a close second in 2:12. Most of his races
were won in the same front shoes it took to balance him, and yet
some writers will say you cannot get immediate results.
XI. SHIN, KNEE AND ARM HITTING PACER.

H. J. Rockwell and Rustler a pacer and trotter respectively, would

hit and cut their boots something terrible. I took H. J. Rockwell away
from his knees by the mode of foot fixing and shoeing hereinbefore
prescribed and that made a race horse of him, whereas he had been
hitting his knees for several years. While he was hitting his knees he
was rated as a quitter, but after he began to beat horses like “B. B.”
over the half-mile tracks, the race followers wanted to know from his
trainer, the late F. M. Dodge, what he had done to him. I mention
this particular case because the public or horsemen that knew this
horse knew he was a tough proposition to balance.
 XII. ELBOW HITTING.

Some horses do this when being speeded. It is caused by excessive

knee action, in folding up of the leg, also in the flexing of the pastern
joint. It is faulty or lost action. For elbow hitting, as a rule, the horse
should be made to go in as light a shoe as possible, he should get his
training with his front feet kept as low as possible at the quarters and
heels and the foot at an angle of about 49 degrees, he should be shod
as light as possible with plain or bar shoes, and with as light a toe
weight as possible, for the more toe weight he carries the harder he
will go to his elbows. Most all elbow hitters hit their elbows with the
toes of the shoe while the knee is being elevated. It would be a hard
matter for a horse to hit his elbows with the heels of the shoes with
the knee extended and elevated, for at this time is when the fold of
the knee and flexing of the pastern causes the toe of the shoe to strike
against the elbow. If preparing the foot for the shoe as stated above
and shoeing the feet light does not stop the elbow hitting apply a bar
shoe with most all the weight in the bar and quarters of the shoe, the
shoe being light as possible around the toe where the nail holes are
punched. Be sure and have the quarters and heels as low as possible.
The reason for low quarters and heels on an elbow hitter is, that it
makes a longer angle to leave the ground from, and it gives a longer
bearing surface behind the leg, to receive the weight that is in the
quarters and bar of the shoe which is put there to prevent some of
the folding of the knee and some of the flexing of the pastern that
causes the interference. I have been very successful shoeing elbow
hitters with this kind of a shoe. All elbow hitters should be worked to
go as low headed as possible, a standing martingale works well on
some. If you put on too much of a toe weight on some horses that go
close to their elbows it will drive their action to, or against their
elbows. Now this being the case, if toe weights will drive him to his
elbows a heel weight will usually prevent folding against the elbows.
 Now in making this shoe for an elbow hitter it will be necessary to
add from four to six ounces more weight to the shoes than he has
been carrying, but put it all in the quarters and bar at the heels, and
keep adding weight to the heels of front shoes until he stops hitting
his elbows. This kind of a shoe is to be used when a very light shoe
fails to prevent elbow hitting. Squaring the toe of the shoe will also
help to lighten the blow, or take him that much farther away from his
elbows.
To decrease the lofty folding action of elbow hitters the foot should
be placed at an angle of from 47 to 49 degrees or as near to that as
possible, and add the amount of weight of shoes he has been carrying
to the toe weight and also add not less than four or five ounces more
to each of a pair of heel weight shoes, when a light one did not
answer. Do not use any toe weight, but if the heel weight bar shoes
are not heavy enough, a heavier shoe or quarter boot can be used.
One thing that should not be overlooked in a horse hitting his
elbows is his hind action, it should be examined closely. The hind
action may be too dwelling gaited, the stride may be too short or too
long. Now if the hind action is of a sluggish nature, it will be a benefit
to increase his propelling power, it will drive his elbow an inch, more
or less, away from the flexing of the foot against it. If he is long and
dwelly gaited you can quicken or make him more rapid, if he is
striding too short you can lengthen his stride by fixing his feet and
applying weight. It is very important to increase his propelling
power. A horse that hits his elbows needs to be balanced by foot
fixing, and the applying of weight to go on as light a line as possible,
because the harder he pulls on the bit when at speed the more he is
inclined to hit his elbows.
If the hind stride is too long and dwelly, shorten the hind toes
considerably and use a square toe shoe and raise the heels with a side
calk. If the hind stride is too short lower the quarters and heels of the
hind feet as much as they will stand and add two or three ounces
more weight to the hind shoes. With toe and heel calks a horse with a
long cannon bone, with lofty action that flexes his foot from the
ground with a snap is more likely to hit his elbows than a horse with
shorter cannon bones.
 XIII. AN UNUSUAL CASE OF ELBOW
HITTING.

A horse that hits the right elbow with the left foot and the left
elbow with the right foot is seldom seen. The horse Hunter Hill
would begin doing this when going at a 2:40 gait or better, and
would act bad and unsteady. He was brought to me to shoe and I was
told he could not carry any weight. As he had not enough foot to
change, I told the trainer he would have to carry weight to counteract
the faulty winging in to the elbows. I made a pair of eighteen ounce
heavy side weight shoes with the weight on the inside of each front
shoe, thin heel and toe calks, toe calks well set back on toe of front
shoes. These shoes took him away from his elbows and he raced good
over the half-mile tracks stepping miles around 2:12. After he got
gaited these sideweight shoes were discarded for plain lighter shoes.
 XIV. PADDLING.

Just the reverse to winging in, a tiresome lost motion, a source of

worry to horse and driver, especially if the horse has speed and is
driven on sharp turns on half-mile tracks, but it is not as dangerous
as the winging in hard to knees. Paddling is more easily controlled
than winging in. Now to straighten the paddler, fix the foot on the leg
that paddles, by cutting or rasping the inside of the foot from the
inside toe back to the inside heel as low as possible, leaving the
outside toe the highest or longest to leave the ground from. Be sure
and have the inside of foot the lowest, the outside toe the longest. To
begin this an angle close to 50 degrees or less, say 49, will have
wonderful effect. The long or high toe on the outside will have a
tendency to make the leg wing towards his knees at speed which is
the controlling influence against paddling. The long or high outside
toe is the part that has to leave the ground the last, which creates
winging, and helps to stop paddling. To shoe a paddler, shoe with a
light shoe, with as little weight as possible to go balanced. The more
weight the more he will paddle, the less weight the less paddle.
The best shoe for a bad paddler is a sideweight shoe extra heavy on
the outside of foot, bevel the outside edges of front shoes good. If the
change of action is not quick enough you can use a toe weight placed
on the foot well to the outside toe of foot. When I could not get the
inside of foot low enough compared with the outside of foot I have
made the front shoes thicker on the outside than the inside. When
you have fixed the feet and shod a paddler this way you will begin to
think that paddling can be stopped when at speed. Most paddlers
must go as light in front as possible. With the feet fixed and shod as
herein stated you will be surprised at the change of action that will
take place when at speed, after a week’s driving. The faster the
paddler is driven the less paddling he will be doing. The outside of
the foot on a paddler needs to be kept the highest, which is just to the
reverse of a knee and arm hitter, this applies to the front feet and
action of the front legs.
 XV. HOW TO MAKE A SHOE TO PREVENT
PADDLING.

Take a piece of iron or steel two or three ounces heavier than the
shoe the horse has been carrying and draw one end of it very light
having it quite thin. Make a heavy outside weight shoe of it, leaving
all the thickness at the outside toe of shoe, thin the outside heel
down to the same as the inside heel. The outside edge of this shoe
will be thick, but tapering thin to the inside edge of the outside web
of shoe. This shoe begins to get light, narrow and very thin at centre
of toe around to inside heel. Look up article on foot fixing to prevent
paddling at speed when using this shoe. The horse’s foot will have to
leave the ground from the outside toe of this shoe when stepping fast
and this will have a tendency to make him wing in, and the line of
action will become straighter as the animal becomes accustomed to
it. This change can be quite radical, on a horse that has been
paddling a long time, and not so rank on young stock just beginning
to get gaited. This shoe does not stop the paddling on all animals
when jogging slow as the foot can leave the ground or break over
from center or inside toe of shoe, which has no control to prevent a
slight paddle.
 XVI. HITCHING, HOPPING OR RUNNING
BEHIND.

This way of going comes from different causes. An unbalanced foot

from being improperly fixed, will cause it. The improper weight of
shoes at one end or the other, or all around, will cause it; speeding a
colt or horse that is pulling too much weight, especially up a grade,
will cause it; forging, scalping, speedy cutting, shin and hock hitting
will cause it; carrying the head to one side at times will cause it;
soreness of the back, rump or muscles of whirlbone, stifle or thigh
will cause it.
Examine the faulty leg for soreness, for if the horse is not lame
from soreness somewhere, he can be balanced to go true. If a horse
begins hitching, his fast work should be stopped until he is properly
balanced, for no horse can improve his speed after he becomes rough
gaited without danger to himself. The first thing to do is to get him
balanced. First, see that his feet are level. Nine times out of ten you
will find his feet are not mates or do not hang level, you will find the
foot on the offending leg that is doing the damage different from its
mate. In all my experience I have found the foot on the faulty gaited
leg to be very high on the inside, if not at the toe, it would be at the
heel, but the majority of times it would be high from toe to heel,
which would be the main cause of the hitching. Fix the front feet to
hang level, the angle and length of toes the same. The two hind feet
should be at the same angle and have the same length of toe. The foot
of the faulty going leg should be made the lowest on the inside and
the shoe to be used on this foot must weigh double the weight or
from one to three ounces more than double the weight of the one on
the opposite hind foot. This shoe can be made with the weight in the
outside, with the inside edge from the centre of toe back to the inside
quarter rounded or beveled off considerably, fit the shoe full to the
outside toe. If the hitching horse is shod according to these
directions and does not begin to go better gaited, it is because he is
lame. If he carries five-ounce shoes behind put twelve or thirteen
ounce on the faulty gaited leg and the light shoe on perfect gaited leg.
 XVII. FORGING.

This is a very annoying fault and the same rules to remedy it do

not apply to all horses, for what will stop one may not stop another.
Most all forging will be done jogging, or going an ordinary road gait.
From forging comes the scalping which is very dangerous when the
horse begins to brush along, as scalping creates rough and bad gaited
horses. There are many horses that will forge or scalp going slow in
the same shoes that suit them for speed. It is hard to shoe all horses
with a set of shoes that will suit the horse, the driver and a faulty gait
at varying rates of speed, all at the same time. Horses that are low
gaited in front that forge jogging, need as a rule, a lot more weight in
their front shoes. Horses that go high gaited with lots of knee action
in front that forge require a light shoe. Forgers usually have excessive
action either in front or behind. Locate the faulty end, see if the horse
has too much action in front and not enough behind, or if he has too
much behind and not enough in front. Get a line on his gait before
you make any changes, perhaps you may not have to change but one
end of him to either increase or decrease action. Weight in the shoe
is the important factor applied to a perfectly balanced foot, whether
it is a front foot or a hind foot. You can add weight to the front or
hind feet, as may be desired, to increase action, or decrease the
weight to decrease the action at either end. Now right here I will say,
a horse jogging hardly feels a change of weight of one, two or three
ounces, but will show the effect of five or six ounces from the start.
Do not be afraid to apply a heavy shoe to hind feet for if his action
requires it to prevent forging, the horse will like it better and so will
you.
In adding weight to hind feet you will be increasing the hock action
and in some horses it will take considerable weight to do it; horses
going an ordinary road gait will not feel one, two or three ounces
increase of weight in hind shoes. Horses stepping fast as a rule do
not do any forging and, of course, the lighter they can go the better.
There are many horses—fast trotters—that forge or scalp jogging,
that would go cleaner or purer by applying a four-ounce toe weight,
some may need a five-ounce weight, lots of them have to be jogged
too fast in order to prevent forging or scalping, when perhaps a toe
weight would be the remedy. A horse going a 2:10 gait will feel the
effects of a one or two ounce weight as much as one going a slow gait
would feel the effects of four or five ounces.
Take a side view of your horse as he is driven by and locate the
faulty action, you will be able to tell if it is too short, too long, too
high or too low, too rapid or too dwelly, front or hind action. If the
lost action is in front as to height, extension or rapidity, fix the feet to
help the shoes to perfect the action. If the front action is too low
shorten the toes, leave the heels high or raise them with shoe or side
calks and shoe with a shoe five or six ounces heavier, more or less, as
the action requires, use a square or bevel toe shoe. A rolling toe shoe
is good on slow-going horses, the horse should carry his head higher
than usual. If the front action is too high, lower the quarters and
heels as low as they will stand, and shoe with a light shoe, and if
there is not extension enough use a toe weight to balance up action,
the horse should carry his head lower, or natural. If the hind action is
too low shorten toes as much as they will stand and add several
ounces more weight and raise the heels a half inch or more. If hind
action is too high lower quarters and heels as low as they will stand,
keeping plenty of toe on hind feet and shoe with a very light shoe to
prevent slipping. If he is handling his hind legs too rapid for the front
ones, this last sentence will remedy that also. I have seen obstinate
forgers at a slow gait stopped by carrying from two to three times
more weight on the hind feet than in the front feet, and vice versa,
according to their front or hind action.
 XVIII. SCALPING.

This is a very dangerous fault. When a horse is making speed and

begins scalping, he is unbalanced quite bad, he needs changing
before being speeded again for if you don’t he or she will get rough
gaited, or will begin carrying the hind leg between front ones,
hopping, or trying to run with hind action. The first thing to do is to
examine the hind feet, you are likely to find the hind feet a lot higher
on the inside than on the outside nine times out of ten. Some horses
will begin scalping after their feet get too long. In horses with
excessive action, carrying too much weight in front will cause
scalping at speed. Horses with very little action in front and not
carrying weight enough will be liable to scalp at speed. When shoeing
for scalping use a square toe shoe, light or heavy, as may be required
by the front action.
Feet all out of proportion and at the wrong angle and not level will
cause scalping. Now if the animal has very little hock action and
mostly stifle action, I would lower and shorten the toes of the hind
feet as much as possible, use a square toe shoe and raise the heels
with a side calk, this will shorten the stride and by adding some
weight to the hind shoe it will increase hock action. Most all scalping
is done with front or outside toe of the front shoe coming in contact
with the coronet of hind foot. It hurts the horse so much that he will
try to find some way to avoid it; some trainers use a gaiting pole to
prevent the horse from going crooked in the shafts because of this
fault.
 XIX. REMEDY FOR SCALPING.

If the front action is low, long and of a sluggish nature, shorten the
toes of feet considerable and add about five ounces more weight to
the shoes, or more, if required to create a more lofty knee fold. The
action of some horses requires a lot more weight than others to make
the change. The shoes to be used, if working to make speed should be
a square toe shoe, or a beveled toe shoe, also a wedged shaped shoe
thick at the heels and thin at the toe is good, squared at the toe. For
ordinary road driving a rolling toe shoe is good, but not for extreme
speed, as it has a tendency with most horses to slip back too much on
leaving the ground; and the horse should be made to carry his head
higher than usual. If the front action is high, short, or too rapid, not
working in harmony with the hind, lower the quarters and heels of
front feet as much as they will stand and keep a fair length toe on the
front feet and shoe with a very light shoe and use a toe weight to
balance for extension, place a spur for toe weight well up on toe of
foot out of way of the scalping; and the horse should be made to go as
low headed as is comfortable to him.
If the hind action is low, long or of a dwelling nature, shorten the
toes as much as they will stand, and shoe, to elevate the heels, with a
thick heel shoe, or raise the heels with side calks. A few ounces more
weight than he has been carrying will be all the better to make him
use his hocks more. If the hind action is high and choppy with not
much extension, lower quarters and heels as much as they will stand
and keep a fair length toe on him, it will keep him closer to the
ground; and shoe light to prevent slipping.
A side view of the animal as he is driven by you will give you the
correct view of his front and hind action. If the action is too short,
too long, too high or too low, in front or behind, the chances are you
may not have to change but one end of him if you have a good eye for
locating faulty action. If your horse is good and can beat his record,
or go the race of his life, and scalps jogging, try a toe weight on him
in front, if it does not stop him wear scalpers on him jogging and let
well enough alone.
I have had to take a three and one-half ounce shoe off a colt that
trotted eighths of a mile in seventeen and a quarter seconds, that was
scalping jogging, and shoe him with a ten and a half ounce heel
weight shoe nailed back near quarters of hind feet to prevent him
from scalping at the jog, after two changes in the front shoeing.
 XX. SIDEWEIGHTS.

Sideweight shoes with the weight on the outside have a different

effect or result on front and hind action. An outside weight shoe on a
front foot has a tendency to make the leg wing in, and an outside
weight shoe on a hind foot will widen and lengthen the stride, if feet
are properly prepared, so you see it widens the hind action and closes
the front action. To close the action of the front leg with this
sideweight, lower the front foot on the inside. To widen the action of
hind leg, lower the inside of hind feet. This sideweight shoe will help
a paddler that has to carry a little weight, if you will lower the inside
of the foot, but it is no good for a knee knocker. The outside weight
shoe has a different effect on front and hind action, has a tendency to
close one and widen the other.
Sideweight shoes are good to correct the following faulty lines of
action if the feet are correctly prepared for them to help the shoe, for
if the foot, or feet, are not properly fixed to help the line of action this
faulty fixed foot will work against the effect of the sideweight, and
the results will be very unsatisfactory. Sideweight shoes are best for
winging in, or paddling out, with front legs, hitching or hopping or
carrying a hind leg in, out of line, or carrying a hind leg between the
front legs, also good for a wheel swinging hind leg.
 XXI. WHEEL SWINGING.

A trotter that is wheel swinging a hind leg, has developed a line of

action that is tiresome, controlled mostly by the muscles on the
outside of leg, that unbalances action at speed to a certain extent,
and it looks unsightly to a good judge of gait, when coming to you or
going from you. To correct this faulty line of action of wheel
swinging, keep the toe of hind feet nearly as long as the front feet,
and have the angle of the hind feet within two or three degrees of the
same as the front feet. If the angle of front feet is fifty degrees have
the angle of the hind feet about fifty-two or three degrees. Lower the
outside of hind foot a full quarter of an inch or more than it will be
on the inside, begin lowering the outside of hind foot at the center of
toe back to outside heel, have both hind feet the same length and
angle. Shoe with a sideweight shoe heaviest side of shoe on inside of
foot, with heelcalks, and place a thin low calk about one inch long on
inside toe of shoe in line from first to second nail holes. After the first
shoeing, if line of action has not improved as it should, you must
lower the outside of hind foot still more, but if you cannot lower the
foot have a shoe made thicker on the inside toe and thinner on the
outside toe and quarters, with the three calks on it and there will be
more of a change. This change can be made in the first shoeing if you
have enough of foot to change, but it is best for the horse and owner
not to make too radical a change too quickly. It is best to do it in two
or three shoeings, especially on a horse that has a lot of speed. Slow
going horses can stand more of a radical change than fast ones.
The directions in this article for the cure of wheel swinging, by foot
fixing and shoeing, will create a sudden change, at different points,
on the bones of the foot and leg, so as to create a leverage at a
particular point as the foot leaves the ground, to control a more
perfect line of action. Be sure your horse is not carrying his head off
to one side, the opposite side to the wheel swinging leg, for if so this
helps to unbalance action and works against the results you are
trying to get to a certain extent. Do not have the outside heel of shoe
any longer than the inside but have both same length.
 XXII. KNUCKLING OVER.

This is caused by weakness, sometimes of the ligaments that hold

the bones of ankle in their sockets, and sometimes higher up. To
shoe for this, the first thing to do is to prepare the foot. You are likely
to find the hind feet abnormally long, perhaps longer than the front
feet. Lower the toes of hind feet as much as they will stand, shorten
toes by rasping off as much as the foot will stand, do not touch the
heels or have the inside of foot higher than the outside. Now use a
light hind shoe, with side calks, the calks to be one and a half to two
inches long, and tapering towards the toe of shoe. At the point of heel
this calk should be not less than one-half inch high, the higher the
better, a square toe shoe is much better than a plain one, shod this
way the very best result is obtained at once. A shoe made thick at
heels, three-quarters of an inch or more, and thin at the toe for
ordinary driving is good.
 XXIII. STUMBLING.

Is a very dangerous fault and is from a weakness that can be

helped a lot. The front feet of a stumbler should be kept as short as
possible at the toe. Elevate the heels as much as would be
comfortable to the leg and horse. A stumbler should be made to carry
some weight in his front shoes because the weight increases knee
action, and this is what you want in a stumbler. Shoe with a
toeweight shoe thick at the heels, for height, and roll the toes of the
shoes as much as possible, a bevel toed shoe is also good, keep the
heels middling high, and the toes cut down low and shortened up.
These shoes are not very good for fast work, as they will slip back too
much on leaving the ground, which retards speed but will help to
make speed in lots of slow ones that require action.
 XXIV. SPEEDY CUTTING.

A horse that is taking his work and is “speed cutting” and still
continues to be a good actor must be game. Speed cutting begins at
the coronet or a little higher up and continues up the pastern mostly
on the inside of leg to the top of ankle and even above that. There are
three things that cause this, the most prominent one to look for, is
the inside of the hind feet are a lot higher than the outside; seven
times out of ten the outside of front feet will be found longer or
higher than the inside. The horse may or may not be carrying the
proper weight. If he is pulling a part of a ton on the bit to hold him
together, he is not properly balanced with weight. The hitting is
mostly done with the outside toe of the front shoe. If you can find
some one who can level and balance these feet on the legs there will
be a big change in the action.
Excessive front, and not enough of hind, action will cause speed
cutting. Excessive hock and stifle action and not enough action in
front will also cause it. When the action is excessive, decrease it by
lowering the quarters and heels and by shoeing very light, if the
action of the other end needs to be increased, shorten the toes and
add weight, do not be afraid, four to five ounces will be better to
experiment with than one or two. After the horse gains confidence he
may not need any extra weight. The most important thing will be to
find some one who can fix the feet, and the feet will be found as I
have stated above. There are very few who are good judges of a
balanced foot. It takes an expert to detect the high and low side of a
foot. Horses that wing into their knees and those that paddle away
from their knees, and line trotters, contract this fault because of an
improperly prepared foot to control the faulty line of action and at
times not carrying the proper amount of weight front and hind to
balance the action so that the hind action will work in harmony with
the front.
If the horse wings in toward his knees with one or both front feet
fix the front feet according to the directions in this book in the
chapter on winging in or knee hitting. If the horse paddles out away
from his knees, I refer you to the chapter on Paddling to prepare his
feet by, and use the shoes therein prescribed. If the front action is
excessive and lofty you must lower the quarters and heels to give him
a longer leverage to leave the ground from, and shoe with a light
shoe, and balance him with a toe weight for extension, and have the
feet the same length and angle.
To prepare the feet on a speedy cutter, rasp down or lower the
inside of foot from centre of toe back to inside heel to a level or a
fraction lower than the outside of the foot, have the toes of both feet
the same length, and at the angle he shows the most speed with.
Shoe with a sideweight shoe, the heavy side of shoe on the outside of
foot and calked to prevent slipping.
To shorten the hind stride use a light shoe, raise the heels and
shorten the toes of the hind feet as much as they will stand. To
lengthen the stride of the hind feet, lower the quarters and heels to a
longer angle to leave the ground from, and add several ounces more
weight than the horse has been carrying to each shoe; the inside
edges of hind shoes from the toe back to quarters should be beveled
off. The edges of front shoes should be beveled off on both outside
and inside.
 XXV. A BAD SPEEDY CUTTER.

The late Freeman M. Dodge of Pittsfield, Mass., trainer and driver,

had a bay mare by the name of “Tillie Wilkes” that was speedy
cutting so bad that he was not able to work her, and he came to me to
find out if I could stop her from speedy cutting. I told him I could not
tell until I saw her driven. He brought her over and drove her down
the stretch at a three minute gait. This mare had a sore spot on the
lower inside of one hind ankle that was raw, the size of a silver dollar
and when she began touching this spot, speedy cutting, she would
jump and begin running. After seeing this mare driven I found she
had excessive action in front and very lofty, and her hind action
mostly all stifle action and very little hock action and her feet were in
bad shape. She was driven over the next day to be shod and I had her
shoes ready when she arrived. I fixed this mare’s front feet by
lowering her quarters and heels as much as nature would allow me,
and left all the toe possible. This gave her a longer leverage to leave
the ground from, which kept her from breaking over so quick, and it
reduced her lofty knee action and created more extension. I took off
a twelve-ounce shoe from each of her front feet, and applied a four-
ounce aluminum shoe.
Fixing her hind feet and shoeing them was the most important. I
shortened the toes and lowered the inside of each hind foot until the
inside of them was as low as the outside or a shade lower if anything.
I fitted a pair of heavy sideweight shoes, the heavy side of the shoes
on the outside of the hind feet, each hind shoe weighed about eleven
ounces with heel calks. This job stopped all the speedy cutting and
she trotted quarters in 31 seconds shortly after, and was sold to Mr.
Shults for $750.00.
 XXVI. GAITING COLTS.

Sometimes you will find a colt that has not much knee, hock or
stifle action and not much speed, and in such cases, to remedy the
defect, after the feet have been leveled the hind feet a shade shorter
than the front, I would recommend a heavy rolling toe shoe in front,
eight, nine or ten ounces and a little lighter one behind, two or three
ounces lighter. If the foot is large and the colt is strong, eleven
ounces in front to begin with. Now as the action increases, decrease
the weight. When the colt begins to make speed he or she will not
need a rolling toe shoe in front, a plain shoe is better, one that will
not slip back on leaving the ground. As the colt begins to make speed
the action of the legs needs watching because sometimes they will
begin to show a faulty line of action.
If they begin to get faulty they are liable to begin winging in or
paddling out, and when shod again the feet can be fixed to prevent
this way of going at speed. The most important thing is fixing their
feet to prevent a faulty line of action for if the feet are not kept level
they will begin getting rough gaited and unsteady. One important
thing in fixing feet on yearlings to be shod and worked for speed is to
keep the quarters and heels of front feet as low as possible, it affords
comfort in landing and increases extension without carrying so much
weight. Colts that have a lot of action at both ends, hind and front,
need very light shoes all round, you can find out the proper balance
with a toe weight.
To increase extension, lower the quarters and heels and apply toe
weights instead of using so much in the shoe. The colt should carry a
natural head, not too high and not too low, the lower the better if he
is inclined to mix. If your colt is short and choppy gaited in his hind
action lower the quarters and heels of hind feet and shoe with a
heavy toeweight plain shoe and extend the shoe out one-quarter of
an inch or more in front of toe of hind foot. When the colt begins to
make speed decrease the weight of shoe of hind feet. Some
youngsters require more weight behind than in front to equalize
action so as to work harmoniously front and rear.
If you have a mixed-gaited colt and you want to make a trotter out
of him or her, keep plenty of foot on both hind and front feet,
especially at the toes. When fixing the feet to be shod cut or rasp the
quarters and heels of both front and hind feet as low as possible,
keep plenty of toe on front and hind feet. Usually you will find that
the front feet have the longest angle to leave the ground from, but by
lowering the quarters and heels of hind feet to get them as near as
you can to the same angle of the front feet, the more you will be
confining the gait to a pure trot, and there will be less danger of
singlefooting or pacing.
I want my readers to distinctly understand that there is a set of
pacing feet for a pacer and a set of trotting feet for a trotter,
especially at the time when you are going to convert a trotter to the
pace or a pacer to the trot. That, however, will be explained later in
this book. If your trotting colt becomes mixed gaited or goes into a
singlefoot or pace, the first thing to do is to lower the quarters and
heels of hind feet as much as possible, keep all the toe on him you
can and shoe with a light shoe with toe and heel calks. The front feet
should be lowered in the same manner and add a few ounces more
weight to front shoes and allow your colt to be driven as low headed
as is comfortable.
When you try this remedy for a mixed-gaited colt or horse you will
be surprised why you have not been able to find it out years ago.
The pacing youngster with not much of any kind of action at either
end, needs to go in short toes and heavy shoes all around and if the
toes of shoes are beveled or rolled it will be very good the first time
shod. After your pacing colt begins to make speed, shoe to prevent
slipping at both ends, with heel and toe calks on hind shoes. As a rule
they go high headed, it seems to suit the majority of pacers.
 HORSE-SHOE STACK—ALLEN
FARM, 1916.

W. J. Moore

If your pacer begins to cross-fire lower the inside of hind feet but if
you cannot lower the feet on the inside raise the outside with the
thickness of the shoe, thick on outside and thin on inside. If you can
lower the inside of hind feet low enough, a plain shoe will do with
calks. The best shoe for a cross-firing pacer is a heavy sideweight
shoe, thin and rounded off on the inside toe. You do not need any
projections on this shoe, heel or toe, if the foot is properly prepared
to widen action. If your colt gets to winging to his knees, lower the
outside of front feet from centre of toes to heel on outside. If your
colt begins to paddle with one front leg or the other, lower the inside
of the foot or feet as much as they will stand, this will leave the
outside toe the longest to leave the ground from, which, when at
speed, will prevent a lot of paddling. The lighter the shoes on a
paddler the better, but if he has to carry some weight in his shoes to
balance action, put all the weight in the outside of his shoes. If you
use a toeweight, attach it near to the outside toe for better results.
Paddling is caused by the contraction of muscles on one side of the
leg, the same as winging in, and not always by bad shoeing, the main
thing is foot fixing.
Some say there is nothing under the sun perfect. Foals developing
in the womb of their dam sometimes will be in a cramped position,
which contracts those muscles or ligaments that cause winging in or
paddling out. As some of the yearlings and weanlings show this
faulty line of action before ever being shod. I have seen yearlings that
were knee-knockers to begin with and you would think confirmed
ones and after one, two or three shoeings you could not hear them
knock their boots on the turns, and they would later develop into fast
trotters and win races or take fast records at two and three years old.
At the Allen Farm, where I have been located for a great many
years, I have seen results obtained by foot fixing and shoeing that
satisfied me that there were secrets hidden from most of the public in
the art or science of foot fixing and balancing faulty action, and from
my experience and the results obtained, I felt that the public was
entitled to my knowledge so gained. I have seen yearlings step
eighths of a mile from 15¾ to 17 and 18 seconds, and many of them.
I have seen a yearling step the last sixteenth of an eighth in seven
seconds, a 1:52 gait, on this half-mile track which should go a second
faster on a mile track.
Now if the foot fixing and shoeing that I have explained in this
book and have been practising for years is not the nearest approach
to the proper and correct way of balancing the action of the trotter
and pacer, why has Bingara become the champion fourteen-year-old
sire of 2:30 performers, located as he is in this cold climate and far
away from the section where are the greatest number of producing
dams? Mares by Kremlin 2:07¾, the champion living brood mare
sire of the world, have produced wonderful results. Through these
channels came Baden 2:05¼, a trotting race horse that raced on
both half-mile tracks and mile tracks and was badly handicapped in
many of his races by being scored ten, twelve, fifteen, and as many as
seventeen times before getting the word. This scoring was not all
done by one driver or one horse, but by different drivers and
different horses trying to break the horse’s heart repeatedly, and
when they could not rupture his legs, unhinge his back, rattle his
thinking box or break his heart, Mr. Geers and Mr. Cox, the great
race drivers, said that Baden 2:05¼ was the greatest race horse ever
seen. In all my experience with the produce of Bingara I have never
seen one yet that wanted to pace if looked after in his early
education. I know him to get trotters from pacing mares, and
nothing but trotters from all kinds of mares, his power to transmit
the trotting gait to his produce is something wonderful, and his only
pacers are those that were forced by the unsportsmanlike use of
hopples.
 XXVII. NEGLECTED HIND FEET.

The hind feet on both trotters and pacers are the worst neglected
when receiving their preparation in training and racing. Is your
trotter or pacer going rough gaited with his hind legs? Is your trotter
hitting his coronets, is he speedy cutting, is he hitting his shins or
hocks? Is your pacer hitting his front shoes, or cross-firing? All this
unbalanced action comes from an unbalanced, unprepared, and
unweighted foot, most times—nearly nine out of ten—from cutting
the outside of hind foot too low from center of toe back to outside
heel leaving the inside the highest, which will control the line of
action of the leg after the foot leaves the ground.
Lots of people do not know this and lots of horsemen do not know
this until they get into trouble and commence experimenting with
some fandangle shoes, long heels on one side and short heels on the
opposite side, or some projection on some part of shoes that creates
strain and friction trying to overcome a badly fixed foot or feet. If
your trotter or pacer is doing any of the above stunts, the insides of
his hind foot or feet are a lot too high for the outside. Cut the inside
of hind feet down as low as they will stand, low enough to change the
angle of the feet, to make the feet or angle longer to leave the ground
from. If his toes are the right length do not touch them.
The best shoe for your trotter in this case is a sideweight shoe, a
little heavier than he has been carrying—two or three ounces heavier.
The best shoe for the pacer is a sideweight, same as above and it can
be an ounce heavier than above, say four ounces heavier than he had
been carrying. After your trotter or pacer becomes purer gaited you
can dispense with this extra weight. Shoe light and as long as the foot
or feet are kept level and at the right poise and angle you will not
have any trouble. I do not recommend shoes with a long heel on one
side and a short one on an opposite side on a correctly or properly
fixed foot, or feet, for fast work or racing, because such shoes create
undue friction at speed. When a hind leg is extended and foot or feet
are properly fixed and balanced on the leg, both heels of the foot
should strike the ground at the same time. If the heel on one side of
shoe is three-quarter of an inch longer, or half inch longer, this long
heel hits the ground first, before the opposite heel hits, which is
unnatural and disagreeable to the bones of the feet, that work in
sockets. It has the tendency to shift the bearing of the bones in their
sockets on landing and leaving the ground, and gives extra work to
the ligaments that hold the bones in their sockets. On slow-going
horses this long outside heel does not affect them as severely as on
horses that are working fast or racing. You must remember when
horses are going at a fast pace they land on their heels as a rule with
their toes elevated away from the ground. This is one of the main
reasons why the heels of hind shoes should be the same length on
both sides at speed or taking fast work. There are lots of horses that
would have been faster and better race horses if their hind feet and
action had been properly balanced to work harmoniously with one
another. The speed of a horse depends largely on the propelling
power of the hind quarters. The muscles of the thigh, stifle and
whirlbone need looking after in their early preparation to keep the
soreness out of them until they become hardened. Do not work your
horse on a slippery track, wait a day or you may be sorry, if he is not
eating skip a workout, it will suit the horse.
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