Hormones And Behaviour Midterm 3 Flashcards

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Growth factors

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-are peptides/proteins which stimulate cells to divide or increase in size (hypertrophy), thus regulate cell growth.

-Most growth factors have autocrine or paracrine actions; they are synthesized, secreted and
act locally.

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Trophic factors

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-are which regulate cell differentiation,, survival, phenotype expression and plasticity as well as growth, which can be growth factors.

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Neurotrophic factors

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-stimulate the growth of neural cells

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Somatotrophic factors

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-stimulate the growth of somatic (body) cells.

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Cytokine growth factors

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-regulate growth and multiplication of
immune system cells.

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Neurotrophic Factors:

Nerve Growth Factor (NGF)

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-promotes axon growth and survival of neurons in the SNS and some sensory CNS neurons.

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Neurotrophin 3 (NT-3)

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-Promotes growth of hippocampal neurons, somatosensory neurons, and cerebellar neurons.

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Neurotrophin 4/5 (NT-4/5)

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-promotes growth of sensory and motor neurons

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Neurotrophin 6 (NT-6)

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-Similar to NGF, but less potent; promotes growth of sensory and SNS nerves.

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Brain Derived Neurotrophic Factor (BDNF)

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-Promotes growth of peripheral sensory neurons and CNS neurons which do not respond to NGF.

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Ciliary Neurotrophic Factor (CNTF)

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-Promotes growth of SNS, PNS and sensory
neurons.

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Glial Cell Line Derived Neurotrophic Factor (GDNF)

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-enhances survival of midbrain dopaminergic neurons

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Somatotrophic Factors:

Epidermal Growth Factor (EGF)

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-Stimulates cell division in epidermal and certain other cells.

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Fibroblast Growth Factors (FGFs)

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-Stimulates proliferation of fibroblasts, endothelial cells and other cell typesincluding blood vessels, neurons and adrenal cells. Found in the pituitary gland.

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Platelet-Derived Growth Factor (PDFG)

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-Stimulates proliferation of connective
tissue cells and neuroglial cells.

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Transforming Growth Factor Beta (TGF-b)

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-Potentiates or inhibits the responses
of most cells to other growth factors.

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Insulin-like Growth Factors (IGF-I and IGF-II)

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-Somatomedins - stimulate proliferation of fat and connective tissue cells.

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Cytokine Growth Factors:

Interleukin 3 (IL-3)

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-stimulates stem cell differentiation.

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Granulocyte Colony Stimulating Factor (G-CSF)

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-Stimulates granulocyte/macrophage progenitor cells and neutrophils

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Macrophage Colony Stimulating Factor (M-CSF)

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-Stimulates granulocyte/macrophage progenitor cells and macrophages.

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Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF)

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-stimulates granulocyte/macrophage progenitor cells.

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Other cell growth stimulating factors

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Neurotransmitters
Neuropeptides
Peptide hormones
Steroid hormones

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Anabolic

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-construction of molecules from smaller units

--building up organs or tissues

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Catabolic

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-large molecules are broken down into smaller units

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Metabolic

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-shaping one molecule into another

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Effect of NGF on SNS growth

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Injection of NGF in the brain causes abnormal growth in the dorsal-root ganglion extending from the spinal cord, in the SNS fibers.

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More Examples of Growth Factors

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Mast Cell Growth Factor (MGS)
Cholinergic Neuronal Differentiation Factor (CDF)
Muscle-Derived Growth Factors (MDGF)
Neurite Inducing Factor
Stem Cell Factor

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Extracellular matrix/adhesion factors

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Nerve Cell Adhesion Molecules (NCAMs)
Integrins
Fibronectin
Gangliosides
Laminin
Apolipoproteins
Neuregulins

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The example in Figure 2.4 shows the activation of membrane associated phospholipase C that results in the formation of diacylglycerol (DAG) and inositoltriphosphate (IP3) from phosphatidylinositol-diphosphate (PlP2). These events lead to the activation of protein kinases and calcium mobilization in the cell, resulting in
the activation of many enzyme systems. Also, calcium-induced elevation of calmodulin levels temporally coincides with the progression of cells from G1 to S phase. Mitogen activated protein (MAP) kinase, presumed to play an important role in the regulation of the early to mid G1 events in the cell cycle, is also activated by growth factor receptor activation.

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Figure 2.2 shows NGF binding to a tyrosine kinase (TrkA) receptor and activating the MEK- MAP-kinase intracellular second messenger system. Epidermal Growth Factor can bind to four different types of tyrosine kinase receptors to activate a number of different intracellular messengers, including PlP2, JAK-STAT, MEKERK and JNK signal transduction pathways, as shown in Figure 2.3.

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Growth factor receptors in the hippocampus. The distribution of growth factor receptors in the hippocampus, as shown in coronal sections on the right side of the rat brain. All distributions are in neurons, with the exception the TGFa precursor, which is localized in glia. The top left panel indicates the regions of the hippocampus, including the dentate gyrus (DG) with its molecular (m), granule cell (G) and hilar cell (H or CA4) layers. Ammon's horn indicates the CA1, CA2, and CA3 regions, each with an alveus (A), stratum oriens (O), pyramidal layer (P), stratum radiatum (R), and stratum lacunosum (L). The fasciola cinerium (FC) is also illustrated.

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Ten ways that growth factors can activate biochemical changes in cells.

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1) The DNA content of the developing brain gives a measure of cell number, reflecting the difference between cell formation and cell death.

2) The metabolic activity of the cell can be measured by its uptake of glucose, oxygen or other ions.

3) The development of cell membrane can be measured by the level of fatty acids taken up as membrane components. The biosynthetic activity of the cell can be measured by:

4) the level of RNA synthesized;

5) the uptake of amino acids;

6) the increase in specific biosynthetic enzymes; or

7) the increase in protein synthesis. The readiness of the nerve cell for functional activity can be determined by measuring:

8a) the number of synaptic receptors for neurotransmitters;

8b) the number of receptors for neuropeptides and non-steroid hormones, or

8c) the number of steroid hormone receptors. Likewise, the amount of neurotransmitter stored in the vesicles

9) and the level of transmitter and other hormone and neuropeptide metabolites

10) in the cell can be used as measures of the functional readiness of the nerve cell

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How growth factors stimulate cell survival and proliferation. Insulin-like growth factor-1 (IGF-1) and interleukin-4 (IL-4) promote cell survival by binding to their receptors, activating second messenger systems which stimulate the production of early onset oncogenes (c-fos, c-myc, c-jun). These oncogenes then stimulate increased metabolism, the expression of genes which stimulate protein synthesis, or changes to the cytoskeleton. Depending on the specific growth factor, its receptor and differentiation status of the cell, the growth factors may stimulate cell survival or proliferation. For example, growth factors may promote survival of immature cells and proliferation of mature cells.

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The role of growth factors in cell differentiation. The bipotential precursor cells of the neural crest are plastic in their development and may differentiate into neural or endocrine cells.

A) In the sympathetic nerve ganglia, fibroblast growth factor (FGF) induces the development of neurons whose axonal projections extend toward peripheral target cells. The release of nerve growth factor from these target cells promotes synapse formation and the survival and maturation of these neurons.

B) In the adrenal cortex, glucocorticoids (GC) inhibit the neural differentiation of the progenitor cells, which are then stimulated by GFG to develop into mature endocrine gland cells.

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Mechanisms for promoting cell death (apoptosis). There are a number of mechanisms for deleting cells.

Cytotoxic T cells, Tumor Necrosis Factor (TNF) and cell surface antigens (Fas, APO 1) can cause cell death directly. Glucocorticoids may stimulate apoptosis by activating genes which trigger cell death. Likewise, T cell receptor stimulation and agents which cause damage to the cellular DNA can stimulate apoptosis by activating cell death genes. The tumor suppressor gene (p53) and the proto-oncogene c-myc, whic regulates cell growth, may both be involved in triggering apoptosis when activated by external modulators such as glucocorticoids. BUT, activation of the "survival" oncogene bcl-2, results in the expression of proteins which may inhibit apoptosis and facilitate cell survival. Certain growth factors, such as interleukins IL-1, IL-2, and IL-3 may also inhibit apoptosis in their target cells.

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Apoptosis:

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-Programmed cell death

-Deleting unwanted cells (pruning)

-Can be triggered by cytotoxic T cells and tumor necrosis factor (TNF)

-DNA damage and excessive glucocorticoid hormone stimulation - cell death genes (p53)

Growth factors:

-block cell death by blocking actions of p53

-cell survival genes BCL-2

-IL-1, 2, and 3 may also inhibit apoptosis

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A model for the role of BDNF in learning and memory.

1) Neuronal activity increases BDNF gene expression and stimulates BDNF release from presynaptic sites in an activity-dependent manner. BDNF binds to TrkB receptors located on presynaptic and postsynaptic sites, leading to the activation of signal transduction pathways including MAPK and PI3-K.

2) Activation of BDNF/TrkB signaling causes phosphorylation of NMDA receptors.

3) Increase in neurotransmitter release from presynaptic sites, and

4) enhancement of protein synthesis. In addition, BDNP-induced modulation of growth and complexity of dendrites may participate in long-term memory.

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How neurotrophic factors prevent cell death

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Internal genitals of males or females

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Males: vas deferens

Females: Fallopian tubes, uterus

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Hormonal gender

-type of hormone secreted by gonads

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Male: Mainly androgens

Female: Mainly estrogens and progestins

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Accessary sex hormones

-depends on hormone

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Male: Prostate gland, seminal vesicles, ejaculatory ducts

Female: Skene's gland, Bartholin's gland

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External genitals

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Male: Penis, scrotum

Female: Vagina, clitoris, labia

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The human karyotype. Humans have 23 pairs of chromosomes for a total of 46 chromosomes; 22 pairs of autosomes and one pair of sex chromosomes. Females have two X sex chromosomes and males have an X and Y chromosome.

B. The X and Y chromosomes differ in size and in gene content, although they evolved from a homologous pair of genes. The Y chromosome is much smaller than the X chromosome and the sex chromosomes have very few homologous genes. The shared genes are the STS, AMG, ADMI, ZFX/Ym and RPS4 genes and the genes in the pseudoautosomal region (PAR). The three genes on the Y chromosome which are specific to the male are the HYA, ZFY, and SRY genes.

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Genotypic sex determination

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-One of two mechanisms that determine whether ovaries or testes develop.

-This is the mechanism in which genes on the sex chromosomes determine testes/ovaries determination

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Environmental sex determination

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-One of two mechanisms that determine whether ovaries or testes develop.

-Mechanism in which environmental factors, such as temperature, determine testes/ovary development

-Environmental sex determination or
temperature-dependent sex determination also occurs in reptiles, amphibia and fish. For
example, in many lizards, turtles and crocodilians, sex is determined during embryogenesis by the incubation temperature of the eggs, which are laid in the ground. In lizards and alligators, warm temperatures produce males and cool temperatures produce females. In most turtles, males are produced at low temperatures and females at high temperatures

-In fish, some species have genotypic sex determination, some have temperature

dependent sex determination and some species which can change from one sex to the other, depending on environmental conditions. Sex change in fish is regulated primarily by size and social factors: the largest females change to males in all female groups or in groups with few males. The "trigger" for sex change may be
behavioural or a chemical signal (pheromone).

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Sex determination

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The undifferentiated embryonic vertebrate gonad is bipotential: it can develop into
either a testes (male) or an ovary (female). Whether testes or ovaries develop is determined by one of two mechanisms: genotypic sex determination, in which genes on the sex chromosomes determine testes/ovary development; or environmental sex determination, in which environmental factors, such as temperature, determine testes/ovary development.

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Chromosomes in rodents

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There are, however, some species of rodents (eg., wood lemmings, collared lemmings and the Oregon vole) in which females have a Y chromosome and males do not.

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Chromosomes in birds

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In birds, sex is also determined genetically, with males having ZZ sex chromosomes and females having ZW sex chromosomes.

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Chromosomes in reptiles/amphibia/fish

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Many reptiles, amphibia and fish also have genotypic sex determination using either the XX/XY or ZW/ZZ sex chromosomes.

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Regions of the Y chromosome

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In mammals, the Y chromosome is much smaller than the X chromosome and contains three unique gene regions: the male-specific histocompatibility antigen (HYA) genes; the zinc finger (ZFY) gene; and the sex-determining region (SRY) genes.

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What is needed for masculization to occur?

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The Y chromosome contains the testes-determining factor (TDF) genes which must be present for masculinization to occur (Graves, 1994). Page et al. (1987) claimed that the ZFY gene was the TDF gene, but masculinization can occur in the absence of the ZFY gene. Sinclair et al. (1990) identified the SRY gene, which is now believed todetermine testes development (Sultan, et al., 1991; Graves, 1994; Schafer and Goodfellow, 1996). If a 46XY genotypic "male" is missing the top of the Y chromosome carrying the SRY gene, they develop as an infertile phenotypic 46XY female, with streak gonads. Likewise, if a 46XX genotypic "female" carries the SRY gene on one X chromosome, they develop as a phenotypic male.

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How many genes are needed for proper sexual differentiation?

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At least 19 genes may be necessary for proper sexual differentiation and these genes are on the autosomes as well as the X and Y chromosomes. For example, three genes on the Y chromosome (WT1, SF1 and SOX9) are necessary for the development of functional testes and at least one gene on the X chromosome (DSS) is necessary for the
development of functional ovaries.

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Barr bodies

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Only one X chromosome is necessary for female development and the second X
chromosome is inactivated by an unknown mechanism. The inactivated X
chromosome produces chromatin condensations called "Barr bodies" in the nucleus of many cells. 46XX females thus have one Barr body in the cell nucleus while 46XY males, who have only one X chromosome, have no Barr bodies in their cells.

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The undifferentiated gonad is composed of...

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...cells derived from four different types of
embryonic tissue: germ cells, connective tissue cells, supporting cells, and steroid-producing
cells.

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Development of Sertoli cells

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The SRY gene codes for a protein messenger (as yet unknown) that switches on the development of the Sertoli cells from the supporting cells in the undifferentiated gonad. The developing Sertoli cells stimulate the production of sperm from the germ cells, stimulate the differentiation of the steroid-producing cells into Leydig cells which secrete testosterone, and produce Müllerian inhibiting substance which inhibits the development of female internal genitalia. Without the SRY gene, the supporting cells develop into follicular cells, the germ cells produce oocytes, and the steroid-producing cells become theca cells which produce estrogen. The pathway of testes development from the undifferentiated gonad occurs in a number of steps and Figure 3B shows some of the disorders of testes development that can occur in mutant mice.

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The testes determining region of the mouse Y chromosome (Tdy)...

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...is homologous with the TDF region of the human Y chromosome and the sex determining gene of the mouse (Sry) is homologous with the human SRY gene. Female mice having the Sry gene on their
X chromosome are masculinized and males lacking the Sry gene are feminized (Gubby et al., 1990). In male mice, the testes begin to develop between E11 and E12 (11-12 days of
embryonic age), thus the Sry gene must be activated at about this time. Koopman et al
(1990) found that the Sry gene was activated in the urogenital ridge of the mouse embryo
(but noy in the head, viscera or body) on day E10.5 and was no longer active on day E13.5,
thus these 3 days are the critical period for masculinization of the mouse. Injection of the Sry gene into the fertilized egg of a female mouse results in masculinization of the embryo (but not in all cases). The resulting XX male mouse had a normal male reproductive tract without fallopian tube development, indicating that the Sertoli cells and the Leydig cells developed and produced MIS and testosterone as in a normal male mouse. It copulated normally, but had small testes which are unable to produce sperm, thus it was infertile (as are all XX male mice).

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Disorders of sex determination

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A 46XX female having the SRY gene is
masculinized and a 46XY male who is missing the SRY gene is feminized. Consider the case
of patient J.S., reported by Jäger et al. (1990). J.S. was a female with normal female external
genitalia who was diagnosed at age 18 as having amenorrhea (no menstrual cycle), an
absence of female secondary sex characteristics, and hypergonadotropic hpyogonadism (too much LH/FSH secretion and no estrogen secretion). She had only non-functional "streak" gonads and her karotype was determined to be 46XY. Analysis of the amino acid sequence of her DNA revealed that 4 nucleotides of the amino acid sequence for the SRY gene were missing. Thus, the DNA sequence failed to code for the protein necessary for testes differentiation and a female phenotype developed. Many disorders of sex determination may involve only a fragment of the X chromosome or the fragment of the Y chromosome containing the SRY gene, or involve mosaics (Simpson, 1982). The "classical" disorders" of sex determination are defined in terms of the presence or absence of the sex chromosomes (Table 6.2) and this section examines four such disorders: Turner's syndrome (45XO); multiple X syndrome (47XXX or 48XXXX); Klinefelter's syndrome (47XXY or 48XXXY); and multiple Y syndrome (47XYY or 48XYYY). Nielson and Wohlert (1990) found a 78 cases of sex chromosome abnormalities in 34, 910 births (2.2 per 1000 births) with Klinefelter's syndrome being most common and
Turner's syndrome being least common.

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Turner's Syndrome

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Turner described 7 females with sexual
infantilism, a webbing of the neck and short stature. Girls with Turner's Syndrome have
undeveloped "streak" gonads (gonadal dysgenesis), underdeveloped secondary sexual
characteristics (breasts and external genitals) and have no menstrual cycles (Ross, 1990). The
absence of a Barr body led to the discovery of the missing sex chromosme and the karotyping of Turner's syndrome patients as 45XO by Ford et al (1959). In about 70% of cases, the missing sex chromosome comes from the father, so may have been either an X or Y chromosome (Simpson, 1982). Turner's syndrome occurs in about 1 out of 2000 (.5 /1000) births (Nielson and Wohlert, 1990). About 60% of the patients have a single X chromosome while some are
Neuroendocrinology of Development 6 - 7
Gonadal Hormones and Sexual Differentiation 12 March 2010 45XO/46XX mosaics (some cells having one karotype and some the other), and others are missing a fragment of the second X chromosome (Ross, 1990; Simpson, 1982). The ovaries of Turner's Syndrome patients differentiate normally, but by birth they have degenerated to a fibrous tissue without oocytes, indicating that the second X chromosome contains genes necessary for normal ovarian development (see Figure 6.2). These streak gonads fail to secrete sex hormones. Virtually all Turner's syndrome patients have short stature (average height = 137 cm = 4 ft 6 in.), do not go through puberty, and lack a pubertal growth spurt. Most Turner's syndrome patients have a normal adrenarche, thus develop axillary and pubic hair and may appear to have some masculinization due to adrenal androgens (see chapter 12). Estrogen given befor puberty increases height and estrogen given between 13 and 15 years of age facilitates the development of secndary sexual characteristics. In rare cases (only 11 are
documented) patients with Turner's syndrome have functional ovaries and have become
pregnant (see Ross, 1990). Turner's syndrome patients have a number of somatic disorders, including a webbed neck, cardiac abnormalities, kidney abnormalities, thyroid gland disease, and often have elbow dysfunction (cubitus valgus), causing them to hold their arm at an angle (see Ross,
1990; Simpson, 1982). Neurobehavioural development in Turner's syndrome (discussed in chapter 13) is influenced by the absence of both the second X chromosome and the lack of
sex hormones (Reiss, et al., 1993).

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Multiple X Chromosome

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About 1 in 900 girls (1.1/1000) are born with
multiple X chromosomes (47XXX or 48XXXX karotypes). These women are often taller and
thinner than 46XX females, but have normal internal and external genitals, normal puberty
and normal development of secondary sexual characteristics (Ross, 1990). Because only one
X cromosome is activated, however, these women have one extra Barr body for each extra X chromosome.

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Klinefelter's Syndrome (47XX)

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Klinefelter et al. (1942) described 9 men with
gynecomastia (enlarged breasts), aspermatogenesis, and elevated FSH levels. These men had small testes which did not produce sperm and were quite tall. Jacobs and Strong (1959) discovered the presence of an extra X chromosome in these men and determined their 47XXY karotype. Although the majority of Klinefelter's patients have one or more extra X chromosomes (47XXY or 48XXXY), about 10% are 46XY/47XXY mosaics (Simpson, 1982; Ross, 1990). These males have Barr bodies for each extra X chromosome. Klinefelter's syndrome is the second most common genetic disorder in humans (after Down's syndrome - trisomy 21) and occurs in 1 in 600 (1.74/1000) boys born (Nielson and Wohlert, 1990). The Neuroendocrinology of Development 6 - 8 Gonadal Hormones and Sexual Differentiation 12 March 2010
extra X chromosome usually comes from the mother and occurs more frequently in older
mothers (Ross, 1990). Klinefelter's syndrome patients are not usually detected until puberty as they have normal male sex determination and testes development (due to the Y chromosome) but the testes are small and and fail to produce sperm. At puberty normal pubic and axillary hair develop, but testosterone secretion is low, resulting in underdevelopment of the secondary
sex characteristics (small penis size, poor muscle development, lack of facial hair and failure of the voice to deepen), elevated FSH and LH levels, and deterioration of the seminiferous tubules. The pubertal growth spurt is enhanced, resulting in tall stature, and increased estrogen secretion may cause breast development. Testosterone replacement therapy is required for adult masculinization (Simpson, 1982; Ross, 1990).

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XYY Syndrome

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About 1 in 850 (1.18/1000) boys born have extra Y chromosomes, resulting in a 47XYY or 48XYYY karotype. These males have masculine
internal and external genitals and because they have only one X chromosome, they have no
Barr bodies. Their growth rate is accellerated, so they tend to be tall and although puberty is
normal, they have an increased incidence of both gonadal failure and elevated testosterone
levels (Ross, 1990).
In 1965 Jacobs et al. reported that there were significantly more XY males in prison
that would be predicted from their occurrance in the population. This report suggested that
the high frequency of XYY males in prison might be a result of their increased aggressiveness or to mental deficiency, and set off years of research on the effects of the extra Y chromosome on criminality. There was even a novel written called "The XYY Man" by
Royse?. However, a thorough review of the genetics of male prisoners by Witkin et al
(1976) indicated that, although there were a higher proportion of XYY men in prison than
expected (3 per 1000 vs 1 per 1000 in the population), these men were more likely to have poor intellectual function rather than increased aggresiveness. The study of criminality in XYY men provides and interesting case study for those interested in genetics and behaviour.

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Genetic true hermaphrodites

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A true hermaphrodite has both ovarian and
testicular tissue and both male and female external genitalia. Most true hermaphrodites are 46XX (probably with the SRY gene on one X chromosome, Schafer and Goodfellow, 1996),
but some are 46XX/46XY or 46XX/47XXY mosaics (Simpson, 1982). The gonads may
consist of one ovary and one testes (with the testes usually on the right and ovary on the left) or combined "ovotestes" having both ovarian and testes tissue. Sperm are not usually produced, but oocytes are. True hemaphrodites have a penis plus a vagina and uterus and are usually reared as males, although they develop breasts at puberty and many menstruate.

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Sexual differentiation

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Sexual differentiation is the mechanism through which genetically determined sex
becomes translated into different physical, neural and behavioural characteristics through the action of gonadal hormones. Sexual differentiation effects (l) the gonads and internal genital organs, (2) the external genitals, (3) the hypothalamic-pituitary-gonadal negative feedback mechanism, and (4) neural development in the brain and spinal cord. In humans, guinea pigs and monkeys, sexual differentiation is complete before birth, but in rodents, it continues for 5-7 days after birth.

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Differentiation of the internal genital organs

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Before sexual differentiation begins
(at about l.5 months after conception in humans), the gonads are the same in both sexes. In this stage the undifferentiated gonad has both a medulla and a cortex and two sets of ducts, the Wolffian ducts and the Müllerian ducts. These ducts lead to the undifferentiated external genitals, consisting of the uro-genital sinus or genital fold and the genital tubercule (Figure 6.5A). After l l/2 months of fetal age, the gonads begin to differentiate. The Testes
Determining Factor genes on the Y chromosome activates the development of the testes from the medulla of the undifferentiated gonad, which begins to develop before the ovaries. In the male, the Wolffian duct develops into the epididymes and the ductus deferens (vas deferens), the gential tubercule develops into the penis and the urogenital sinus develops into the scrotum (Figure 6.5C). The Müllerian ducts degenerate in the male. In the female, the cortex of the undifferentiated gonad develops into the ovary while the Müllerian ducts develop into the fallopian tubes. The urogenital sinus develops into the uterus and the genital tubercule becomes the vagina and clitoris. The accessory sex glands (Skene's and Bartholin's glands also develop. Without androgen stimulation, the Wolffian ducts and the medulla of the undifferentiated gonad degenerate.

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Gonadal hormone secretion

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As the testes develop, they produce two
hormones: testosterone and Müllerian Inhibitory Factor. Testosterone masculinizes the reproductive system, brain and spinal cord and the hypothalamic-pituitary-gonadal feedback system. Testosterone stimulates the development of the Wolffian ducts, which form the epididymis and vas deferens (or ductus deferens) and the male accessory sex glands. The cortex of the undifferentiated gonad and the Mullerian Ducts degenerate in the male. If
testosterone is absent, as occurs in the female (and in some genetic disorders of males), the
Wolffian ducts fail to develop and the internal genitals are feminized. The prenatal surge in testosterone is not controlled by the hypothalamus and pituitary, but some other mechanism ? What is this mechanism??
Müllerian Inhibitory Factor (MIF) (or Mullerian regression substance) defeminizes the
reproductive system, inhibiting the development of the Müllerian ducts.
During fetal development the ovaries produce low levels of estrogens. Estrogen secretion
from the ovary may or may not be important for feminization of the female (see NYAS,
1986 vol. 474). Gonadal hormone secretion begins at about 60 days of embryonic age in humans (Figure 6. 4) and at about 17.5 days of embryonic age in rabbits (Figure 6. 6). What about rats and mice?

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Differentiation of the external genitalia

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The external genitalia begin to differentiate between 2.5 and 5 months of fetal age (Table 6.3). In the male, androgens cause
Neuroendocrinology of Development 6 - 11
Gonadal Hormones and Sexual Differentiation 12 March 2010 the genital tubercule to develop into the penis and the urogenital sinus or genital swelling closes over to form the scrotum (Figure 6.7). Within the urogenital sinus, the accessory sex glands; the prostate gland, Cowper's glands and the seminal vesicles develop from the urethral primordia (whatever this is). In the female, the genital tubercule forms the clitoris, while the genital folds form the labia and the urogenital sinus remains open to form the vagina (Figure 6.7). The female accessory sex glands. Skenes and Bartholin's glands develop from the urethral primordea of the urogenital sinus. (Money, and Ehrhardt, A.A. Man and woman, boy and girl.

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Differentiation of the hypothalamic-pituitary-gonadal feedback system

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From the
third to eighth month of fetal life in humans and from day E17 to postnatal day 10,
androgens masculinize the hypothalamic-pituitary-gonadal-hormone feedback system (Table
6.3). In the adult male, LH is released continuously from the pituitary and testosterone
synthesis is continuous in the testes, showing only minor daily and yearly cyclic fluctuations.
Testosterone provides negative feedback on LH-RH and LH, so that an increase in
testosterone level will cause a reduction in LH in males (see Brown, 1994). Estrogen injection
will inhibit LH secretion in males. The female hypothalamic-pituitary-gonadal feedback
system is more complex, involving two gonadotrophic hormones, LH and FSH, and two
gonadal hormones, estrogen and progesterone (see Brown, 1994). FSH stimulates estrogen
secretion in the female and estrogen provides positive feedback, stimulating LH-RH and LH
release. Injections of estrogen into females thus elevate LH secretion. The first sex difference
in the H-P-G system, therefore, is that testosterone and estrogen provides negative feedback
to LH-RH and LH in males, but estrogen causes positive feedback on LH-RH and LH in
females.
Second, the female H-P-G system is cyclic, with estrogen-stimulated LH surges
occurring every 4-5 days in rodents or every 28-34 days in humans (Figure 6.8). In the male,
the secretion of H-P-G system is more constant. Masculinization of the male by androgens
during fetal development alters the cyclic pattern of the H-P-G system and changes the
positive feedback of estrogen on LH to the negative feedback of testosterone on LH. The
masculinizing action of testosterone appears to act primarily in the pre-optic area and
hypothalamus. The gonadal hormone feedback system, involving hormone sensitive
neurons in the MPOA-AH, neurotransmitter release and the release of hypothalamic neurohormones from the neurosecretory cells in the median eminence (arcuate nucleus) thus
becomes masculinized by androgens.

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Sexual differentiation of the brain and spinal cord

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Testosterone acts to
"masculinize" specific areas of the brain and spinal cord, resulting in sex differences in a
number of neural and spinal tissues (Table 6. . Testosterone can alter (1) the number of
nerves developing; (2) neurite growth; (3) neuronal size and form; (4) biochemical processes
within target cells; and (5) the sensitivity of neurons to hormones. (Gorski) Using steroid
hormones as an example, Table 12.3 shows five different ways in which neural development
can be hormonally modulated.

Front 70

Alterations in nerve number

Back 70

(a) There are steroid-induced sex differences in neural
number in area RA of the zebra finch brain, and in the rat SNB in the neonatal period. (b)
Androgens prevent SNB neural death, may cause cell differentiation, and may not influence
neurogenesis. (c) Steroids may regulate neuron numbers in adulthood.

Front 71

Steroids influence neurite growth

Back 71

(a) Testosterone and estrogen both stimulate neurite
growth in neonatal hypothalamus. (b) Steroids induce dendritic growth in adult canaries and
in gerbil POA. Same effect in neonatal and adult brain.

Front 72

Sex steroid influence on neuronal size and form

Back 72

(a) Neonatal steroids produce larger RA
in male finches; and larger SDN-POA and SNB in male rats. (b) In adulthood, steroids
increase the size of zebra finch RA neurons; and size of rat SNB motor neurons; steroids can
increase neuronal size in neontatal and adult animals.

Front 73

Sex steroid influence on biochemical processes

Back 73

In both neonatal and adult animals,
steroids alter many enzymes levels, and influence number of receptors for neurotransmitters.

Front 74

Steroid-induced changes in steroid binding and accumulation in cells

Back 74

(a) Neonatal hormones alter the sensitivity of neurons to hormones. (b) Levels of steroid receptors can be influenced by steroids in adulthood.

A. By influencing the number of receptor proteins produced in the cells and thus the
amount of hormone binding to the cells. Receptors for neurotransmitters, hormones or
neuropeptides may all differ between the sexes (examples).

Front 75

Freemartin

Back 75

Farmers who had twins in an animal, one male one female, had a sterile female. This may be because they're in the same environment and some of the blood mixed, the female is exposed to the same chemical environment that the male is, and the female brain develops more of a male pattern. Although she looks reasonably normal, her ovaries are atropic, and her gonads are not present.

Front 76

Why do 2M males show more aggression?

Back 76

2M males show more aggression, due to a higher proportion of estrogen. Males surrounded by two females actually show more sexual behaviour than other types of males.

Front 77

Levels of steroid receptors can be
influenced by steroids in adulthood...

Back 77

....By influening the structure of neural development. This includes (1) modulation of
the growth of the cell, thus altering the size and form of neural cells. (2) Regulating the
number of neurons developing in particular brain areas, mainly the pre-optic area and the
hypothalamus. The sexually dimorphic area of the pre-optic area of the hypothalamus is a
primary example. In rodents, a particular area of the MPOA-AH hypothalamus is masculinized. This sexually dimorphic area is longer in the male than the female and appears to control a number of sexually dimorphic behaviours (Figure 6.10). Sex differences also occur (in rats) in the hippocampus, amygdala and cortex due to fetal organization by androgens. (3) Regulation of neural outgrowths and dendritic branching, thus altering the number of cells connected together and the number of synapses formed.

Front 78

Perinatal manipulation of sexual differentiation

Back 78

Manipulation of gonadal hormone levels during the critical period of sexual
differentiation can alter the masculinization of the internal and external genitals, the H-P-G
feedback system and the neural development of the brain and spinal cord. In humans, guinea
pigs, and primates, this sexual differentiation occurs before birth (Figure 13.3), thus, pre-natal manipulation may alter sexual differentiation. In rodents, however, sexual differentiation continues for up to a week after birth and manipulation of hormone levels at birth can influence sexual differentiation. Such peri-natal (around the time of birth) manipulation can produce masculinization of females and demasculinization of males.

Front 79

Castration of males on the first day after birth...

Back 79

...results in the brain retaining its female
pattern of differentiation. These males are, therefore, both demasculinized and feminized.
Injection of testosterone into female rats on the first day after birth masculinizes and
defeminizes them. Such perinatal hormone treatment can produce truly hermaphroditic rats, with both a penis and a vagina (find photo of this) and can disrupt the sexual differentiation of the brain. The effect of this hormonal manipulation during the "critical period", therefore, is to alter all of the sex differences in the brain.

Front 80

Demasculinization

Back 80

Following the time of puberty, males castrated in infancy show less mounting of females (demasculinization). Males castrated at birth show less rough and tumble play in infancy, are less aggressive, scent mark less, show increased activity levels and more parental behaviour than control males.

Front 81

Feminization

Back 81

If castrated and given estrogen and progestin injections in adulthood, will show female pattern lordosis when mounted by another male (feminization). Control males show masculine behaviour if castrated in adulthood and given either testosterone or estrogen injections.

Front 82

Masculinized females

Back 82

Show more rough and tumble play, are more
likely to show male-like mounting, show less lordosis, more aggression, more scent-marking, lower activity levels and decreased parental behaviour. If fetal males are given a testosterone receptor-blocking chemical such as cyproterone Neuroendocrinology of Development 6 - 15 Gonadal Hormones and Sexual Differentiation 12 March 2010 acetate during the "critical period" of sexual differentiation, no testosterone receptors are available, so the male is "feminized", as though it was castrated. These feminized males develop nipples, and the differentiation of the genital tubercule is inhibited, so that a clitoris develops rather than a penis.

Front 83

Neonatal cyproterone acetate

Back 83

Neonatal cyproterone acetate administration "feminizes" males, by inhibiting hypothalamic organization. Also, cyproterone acetate prevents penis and accessory sex gland development. This requires huge cyproterone acetate doses over long periods of pre- and post-natal development (10 days prenatal, three weeks postnatal).

Front 84

Females masculinized by receiving testosterone

Back 84

If a female has been "masculinized" by receiving testosterone, her clitoris may be enlargd to form a small penis. Male rats given cyproterone acetate and estrogen develop a vagina, show cyclic gonadotrophic secretion system and are treated like females by other males -- yet they are genetically male!

Front 85

When newborn female rats are given testosterone injections...

Back 85

...they have small ovaries, no ovulatory cycle and no ovulation (no formation of corpora lutea) i.e. no LH surge. Castrated newborn male rats given ovarian implants as adults show ovulation (formation of a corpora
lutea), thus have an "LH surge", indicating that the H-P-G feedback system was altered by
prenatal hormone injection. When hormones are injected, there is often a dose-response curve. The more hormone, the stronger the response, thus, the more testosterone injected into the newborn female, the greater the "masculinization" effect. Even though the gonadal hormones have a powerful effect on the development of sexually dimorphic behaviour; this effect can be altered by social experiences during development.

Front 86

Aromatiziation of testosterone

Back 86

Testosterone is converted or aromatized to estradiol by the enzyme aromatase. Thus, in
the neural cells, it is estradiol that serves to masculinize the cells during the "critical period" of the organizational phase. In the external genitals, the penis and scrotum, and the accessory sex gland; testosterone is converted or reduced to DHT by the enzyme 5 alpha reductase. It is the DHT that stimulates cellular activity in these cells.

Front 87

Testosterone can act at its target cells in three ways

Back 87

By directly stimulating testosterone receptors; by aromatization to estrogen and stimulation of estrogen receptors or by reduction to DHT and stimulation of DHT receptors. Aromatization and reduction can only occur in cells which contain the appropriate enzymes. Thus, if aromatase or reductase enzymes are lacking, some aspects of masculinization may fail to occur, while other aspects will occur normally. There are a wide variety of disorders of sexual differentiation which occur because of enzyme deficiences.

Front 88

Prevention of female masculinization

Back 88

There are three reasons why females are not
masculinized by their own estrogens:
(1) There are only very low levels of estrogen secreted by the ovaries of a developing
Neuroendocrinology of Development 6 - 17
Gonadal Hormones and Sexual Differentiation 12 March 2010 female (8 units per hour). There are, on the other hand, 2000 units of testosterone secreted per hour in the developing male (Figure 13.4).
(2) There are very few estrogen receptors in neonatal females. (3) All of the estradiol produced by the ovaries of the perinatal female is bound to a special carrier protein called alphafetoprotein, or fetonatal estrogen binding protein, which is only produced during the critical period of sexual differentiation. It is produced in the liver for the first three weeks of life, and released into the circulation where it binds to all estrogen in the blood and does not let it go free. Thus, there is no "free" estrogen to bind to the receptors and masculinize the female.

Front 89

Alphafetoprotein

Back 89

Alphafetoprotein is present in both males and females, but only binds to estrogen, not testosterone, so does not prevent
masculinization of males. Certain synthetic estrogens do not bind to alphafetoprotein and are thus able to reach the brains of newborn female rats and masculinize them. Synthetic
estrogens given to women during pregnancy may be transferred to the fetus, possibly leading to masculinization and to vaginal and cervical cancer. (e.g.) the target organs "over-respond" to estrogen when the women reaches puberty.

Front 90

Three examples of sexually dimorphic neural circuits

Back 90

There are three examples of sexually dimorphic neural circuits which have been well studied: (1) the sexually dimorphic nucleus of the pre-optic area of the brain of rodents; (2) the spinal nucleus of the bulbocavernosis in rodents, and, (3) the brain regions controlling birdsong.

Front 91

Sexually dimorphic behaviours

Back 91

These sex differences in neural organization of
the brain and spinal cord lead to the development of different male and female patterns of behaviour. Sexually dimorphic behaviours are those that are characteristic of one sex and are shown by one sex more frequently than the other. But, they are not exclusive to one sex. Sexually dimorphic does not mean that the behaviour is only shown by animals or people of one sex and never by those of the other sex.

Front 92

What do the brain and neurotransmitter system begin as?

Back 92

The brain and neurotransmitter system, like the genitals, begins as "undifferentiated"
tissue and if no androgens are present, develops in a female pattern. Under the influence of
neonatal androgens, however, the brain and neuroendocrine system are masculinized.

Front 93

Masculinization appears to function like a rheostat...

Back 93

...you start with a neutral (female)
pattern of cellular development and testosterone modulates this, inducing the male pattern of growth. Masculinization of the brain and neuroendocrine system can be complete or partial, depending on the level of testosterone present during a "critical period" of development. In many cases, there appears to be separate neural systems mediating male and female behaviours. Masculinization may act to promote growth of the male system, while lack of testosterone may allow the female system to develop. In other cases, there is one neural area which is shifted along a continuum from female to male, depending on the level of testosterone present.

Front 94

Most sexually dimorphic behaviours do not emerge until after puberty...

Back 94

...when they are "activated" by the gonadal hormones in adulthood. These sex differences in behaviour include sexual behaviour (proceptive and receptive); aggression; scent-marking; ultrasonic vocalizations; parental behaviour and activity levels.

Front 95

Adrenogenital syndrome

Back 95

There are some people who have an enzyme deficiency in the adrenal cortex, and instead of cortisol being produced, adrenal androgens are synthesized. Progesterone is thus converted to androgens in the adrenal cortex rather than cortisol. Adrenogenital syndrome, or congentital adrenal hyperplasia, has little effect on developing males, who already have high testicular androgen levels, but the high levels of adrenal androgens can partly masculinize females. Thus, a 46 XX genotype with ovaries and fallopian tubes, may have her external genitals fully or partially masculinized, depending on the amount of adrenal androgens produced. In extreme cases, the female is completely masculinized and the gender of rearing is male. In less extreme cases, the genitals can be surgically feminized and the gender of rearing is female. In these less extreme cases, the female may experience a late menarche, but will usually be able to conceive, give birth and lactate (see chapter 18 on gender role and identity). Of course, these females must be given corticosteroid treatment immediately after birth as they produce little or none from their own adrenal cortex. If cortisone therapy is given neonatally, excess androgen production ceases and female puberty and reproductive functions are normal - but menstruation may start late.

Front 96

Testicular Feminizing Syndrome

Back 96

This syndrome, also called androgen
insensitivity syndrome, is caused by a lack of androgen receptors. It is an X-linked recessive
trait in a 46 XY male who is not able to produce androgen receptors. Although the testes
produce normal amounts of androgens, the target cells are insensitive to them. The genetic
male, therefore fails to become masculinized and becomes feminized. He has testes, but the
external genitals are feminine. There is a short vagina, an incomplete uterus and a clitoris
rather than a penis. Such a person is reared as a female and develops female gender identity
and role.

Front 97

Reifenstein's Syndrome

Back 97

This is incomplete androgen insensitivity or partial feminization.

Front 98

Imperato-McGinley Syndrome

Back 98

In this condition, the male lacks the enzyme 5
alpha reductase and there is a failure of the external genitals to be masculinized. The male
thus has testes, vas deferens and semenal vesicles but a vagina and clitoris instead of a penis. At puberty, the rise in testosterone can masculinize these males (Figure 13.14). This was discovered in a few families in South America. At puberty, however, these males develop a penis and scrotom due to high levels of testosterone secreted.

Front 99

Receptor positive resistance

Back 99

The androgen receptor protein has a defect so that the H-R complex can not bind to the chromatin in the nucleus. - or, the hormone-receptor (H-R) complex fails to be accepted on the chromatin.

Front 100

Pseudohermaphrodites

Back 100

Pseudohermaphrodites are more common and have the internal genitals of one sex and
external genitals of the opposite sex (e.g.) ovaries and a penis (Adrenogenital syndrome) or
testes and a vagina (Testicular feminizing syndrome).

Front 101

Hormone treatments in pregnancy

Back 101

If a pregnant female takes external hormone or drug treatments, these external chemicals may interfere with the pregnancy. Those chemicals which alter gonadal steroid hormone levels may cause abnormalities in sexual differentiation in the offspring. If estrogens or androgens are elevated during pregnancy, the body will be masculinized. If DES is taken, still other complications arise in female babies, related to uterine cancer etc. If progestins or anti-androgens are taken during the pregnancy, the baby will be feminized.
These effects occur because the steroid hormones are small enough to diffuse through the placenta and enter the baby's circulatory system. The effects of disorders of sexual differentiation on adult behaviours are discussed in chapter 18 on gender identity and gender role.

Front 102

Activation of the H-P-G system

Back 102

Gonadal steroids reach a peak during the
perinatal organizational phase and then remain low until l0-l2 years of age when
gonadal steroid hormone levels gradually increase to adult levels. During this
activation phase the hormones activate the gonadal hormone receptor pathways
that have been queiscent since their perinatal organization. At puberty gonads enlarge and begin to function and the ability to reproduce
sexually is achieved. In female rats this is measured by the time of vaginal
opening, the first ovulation and first estrus cycle (35-50 days of age). In male rats
puberty is measured by the presence of spermatozoa in the seminiferous tubules
and the ability to show the complete adult copulatory pattern (50-65 days of age).

Front 103

Onset of Puberty Postulated Ontogeny of Hypothalamic-Pituitary-Gonadotropin-Gonadal Circuit:

Fetus

Back 103

a. Secretion of pituitary FSH and LH by 80 days gestation
b. 'Unrestrained' secretion of LRF (l00 to l50 days)
c. Maturation of negative sex steroid feedback mechanism after l50 days gestation
- sex difference
d. Low elve of LRF secretion at term

Front 104

Onset of Puberty Postulated Ontogeny of Hypothalamic-Pituitary-Gonadotropin-Gonadal Circuit:

Infancy and Childhood

Back 104

a. Negative feedback control of FSH and LH secretion highly sensitive to sex
steroids (low set-point); maximum sensitivity attained by 2 to 4 years of age
b. Higher mean serum FSH and LH levels in females.

Front 105

Onset of Puberty Postulated Ontogeny of Hypothalamic-Pituitary-Gonadotropin-Gonadal Circuit:

Late Prepubertal Period

Back 105

a. Decreasing sensitivity of hypothalamic gonadostat to sex. Increased secretion
of LRF steroids (increased set-point)
b. Increased secretion of LRF
c. Increased responsiveness of gonadotropes to LRF
d. Increased secretion of FSH and LH
e. Increased responsiveness of gonad to FSH and LH
f. Increased secretion of gonadal hormones.

Front 106

Onset of Puberty Postulated Ontogeny of Hypothalamic-Pituitary-Gonadotropin-Gonadal Circuit:

Puberty

Back 106

a. Further decrease in sensitivity of negative feedback mechanism to sex steroids
b. Sleep-associated increase in episodic secretion of LH
c. Progressive development of secondary sex characteristics
d. Mid- to late puberty - maturation of positive feedback mechanism and capacity
to exhibit an estrogen-induced LH surge
e. Spermatogenesis in male; ovulation in female

Front 107

There are a number of terms related to puberty that should be defined:

Back 107

Adenarche is the beginning of secretion of adrenal androgens at puberty;
gonadarche - the activation of the hypothalamic-pituitary-gonadal system, which is difficult to measure without looking at hormone levels. The larche is the beginning
of breast and nipple development in females; and Menarche is the first menstrual
period, usually l2.5 - l3.5 years of age.
Measuring the changes occurring at puberty is easier in females than in males because breast development, and menarche provide significant markers to measure the advancement of puberty. Males have no one single event that can be used to determine which stage of puberty has been reached. In males, the size of the testes and the penis are used to determine the stages of puberty. This uses an "orchidometer", which uses a set of "worry beads" to determine testes size. Puberty doesn't occur all at once. There are a number of stages and it is a gradual process.

Front 108

Tanner breast stages by estradiol stages

Back 108

Front 109

Variables influencing the timing of puberty

Back 109

The timing of puberty can be influenced by nutrition, so that overweight people reach puberty sooner than underweight people and anorexics show a delay or inhibition of puberty. Stress is a second variable which influences the timing of puberty. Stress

causes a delay in reaching puberty as it inhibits gonadotrophin secretion. Thus, victims of abuse (psychosocial) dwarfism often show delayed puberty (Chapter 16). Light cycles are a third variable which influence the timing of puberty. Animals kept in long days (16 hr light) will reach puberty earlier than animals kept in the dark or long night (8 hr light) environments. Social odours or "pheromones" from other
animals are a fourth varible which can accelerate or inhibit the timing of puberty
(Chapter 27). Finally, social rearing or housing conditions can also influence puberty as animals reared with their parents or in brother-sister littermate groups after weaning show an inhibition or delay of puberty. Thus, odours and social housing conditions can influence the timing of puberty as well as nutritional, stress
and environmental lighting.

Front 110

Critical weight theory

Back 110

The earliest theory of what controls
the timing of puberty is the critical weight theory. (Figure 17.3a). This theory
suggested that there is a critical weight you had to reach and when you reached
that weight it triggered puberty. In many species the puberty occurs when an animal
reaches a certain weight, irrespective of age (e.g. French vs American girls show
similar characteristics of puberty). The result of this theory is that those people breeding farm animals want them to
grow more rapidly and reach puberty earlier. This theory, however,may be
oversimplified, as the percent body fat, and other factors also control the timing of
puberty.

Front 111

Changes occurring at puberty in females

Back 111

In females, changes begin to be noticed around ll years of age with the onset of breast development (thelarche). Adrenarche is associated with the initiation of pubic hair growth due to adrenal androgens and this is followed by the growth spurt due to a surge of GH. As growth continues, the "critical body weight" occurs and gonadarche begins, with breast enlargement and more abundant pubic
hair. Following the rise in gonadal hormones at gonadarche, the menarche occurs and this is followed by adult breast development and adult sexual hair (pubic and axillary).

Front 112

Changes occuring at puberty in males

Back 112

Male pubertal development is l-2 years behind that of females (why?) In males, puberty begins with the gradual rise in androgen secretion from both adrenal cortex and gonads, resulting in an increase in testes, scrotum and penis size . This is followed by the growth of pubic hair and the growth spurt, 2 years behind the
female. By age l4-l5, males develop adult size testes and penis, pubic and axillary hair growth, and after l6 years of age, beard growth. Erection and nocturnal seminal fluid emission also begin to occur. Thus, puberty in females begins l-2 years before males and females have their growth spurt before the male. Both sexes complete puberty by about l6 years of age. There are a number of individual differences in the timing of puberty as seen
in Figure l7.3 in which the girls are all l2 3/4 years of age and the boys are all l4 3/4
years of age, but all are at different stages of puberty. These may be due t a number of different factors: genetic, nutritional, social and environmental.

Front 113

Activation of the H-P-G
system

Back 113

Activation of the H-P-G system involves increased release of FSH-RH and LH-RH from the hypothalamus, FSH and LH from the adenohypophysis and increased levels of gonadal steroids. Figure l7.4 shows the pattern of pituitary-gonadal hormone release during puberty in males and females, superimposed on a graph of growth rate (i.e. height gain in
cm./year. FSH rises first, at about 9 years of age in females and l0-ll in males. This is followed by LH rises at l0-ll in females and l2-l3 in males, and then by gonadal hormone increases, with estrogen levels showing a rise around age ll in females and testosterone around ll-l2 in males. Note that the growth spurt is associated
with FSH and LH rises in females, but occurs after these in males, being associated
with the rise in testosterone level. Obviously the rise in FSH and LH is triggered by
a rise in hypothalamic FSH-RH and LH-RH release.

Front 114

FSH in puberty

Back 114

Taking a monthly "window" on the hormone changes in puberty, these figures show that prepubertally, there are low levels of FSH, LH estradiol and progesterone. FSH rises first at thelarche and maintains this level at menarche,
and shows typical adult monthly surges 6-9 months after menarche.

Front 115

LH and estradiol in puberty

Back 115

LH remains low at thelarche, begins to rise at menarche and shows adult cyclic fluctuations by a 6-9 months after menarche. Estradiol remains low at thelarche (except for one girl, W), shows some surging at menarche, and adult
patterns 6-9 months after menarche.

Front 116

Progesterone in puberty

Back 116

Progesterone is low through thelarche and menarche and shows adult cyclic patterns by 6-9 months after menarche. It is not until the late stages of puberty (after menarche) that the surges in LH occur which are necesesary for follicle release and ovulation to occur. Note
that subject B still has a low progesterone level here, even though her LH, FSH and
estradiol cycles appear adult (Figure l7.5 and l7.6). This subject appears to have
had an anovulatory cycle, in this case.

Front 117

GH in puberty

Back 117

The changes in GH secretion over a 24 hour
period in a pre-, mid-, and late-pubertal person. This shows the day-night cycle of GH secretion with the sleep-related GH surges becoming more prominant in early and later puberty. Stress can inhibit these surges in GH and thus delay puberty.

Front 118

Effect of LH on sleep

Back 118

Like GH, LH shows a day-night rhythm. In pre-pubertal females, LH is low in both day and night and in early puberty LH shows sleep-related surges or pulses about every 90 min. In later puberty, the nocturnal LH surges begin to
peak and there are daytime LH surges as well. Thus, the initiation of puberty involves the pulsatile secretion of GH and LH from the adenohypophysis and these are both controlled by the hypothalamus and show day-night cycles. The development of this pulsatile release of LH is a critical feature in the timing of puberty.

Front 119

Adult females with anorexia nervosa...

Back 119

...show amenorrhea (inhibition of the
menstrual cycle) also have a decline in LH, so there is no pulsatile release and the LH level is the same as that of a pre-puberty girl (Figure l7.7). Development of secondary sex characteristics. As the gonadal hormones rise, they activate changes in body development, physical features, endocrine changes and
psychological changes. Secondary sex characteristics are the physical, endocrine
and behavioural changes which occur at puberty which differentiate males and
females.

Front 120

The metabolic changes caused by increased
levels of testosterone at puberty

Back 120

These include the development of the external
genitals and secondary sex glands and maturation of spermatogenesis. The size
and weight of the prostate gland and seminal vesicles and sperm count can, therefore, be used as bioassays for testosterone, as they increase in direct proportion to the level of circulating androgens. The weight of the prostate and seminal vesicles is often used to determine the metabolic effects of different
androgens or anti-androgenic drugs.
Androgens also facilitate pubic, anxillary and facial hair growth and cause recession of hair growth on the scalp. Androgens cause deepening of the voice, acceleration of bone and muscle growth; increased sebaceous gland secretion (acne) and reduced subcutaneous fat levels. Androgens also promote sex drive
and regulate negative feedback on the hypothalamic and pituitary hormones. Note: Prepubertal castration inhibits these actions and in particular, the change of the voice. Church choirs used to castrate their best boy singers and songs were written with "soprano", "alto", "bass" and "castrato" voices. Today, the "castrato" parts are usually sung by girls.

Front 121

Estrogens

Back 121

Estrogens increase uterine, vaginal and breast development and influence fat deposition and distribution. There are sex differences in how people get fat - men get beer bellies, women get fat asses and thighs. Estrogen stimulates
bone and skeletal growth, and increases GH release and the levels of carrier proteins (TBG, CBG and SHBG). Estrogen also regulates the negative and positive feedback on the hypothalamic-pituitary hormones and activates sex drive in females.

Front 122

Progesterone

Back 122

Progesterone often depends on the "priming" action of estrogen for its effect. The estrogen acts to prime the target cells, by initiating cell growth, synthesis of enzymes or progesterone receptors, and then progesterone acts on
this primed system to stimulate further cell growth and differentiation. Within the uterine endometrium, progesterone increases cell growth and secretory activity of cervical glands. In the breast, progesterone stimulates
development of alveolar ducts. Progesterone elevates body temperature slightly (by
about l/2 degree C) and provides negative feedback to the hypothalamic and pituitary hormones

Front 123

Gonadal Steroids

Back 123

The gonadal steroids act like growth hormones to promote somatic growth in a number of ways. Gonadal steroids also interact with the hypothalamic-pituitary feedback system and activate neural steroid receptors establishewd during the organizational period. The neural receptors for gonadal steroids are located
primarily in the limbic system and are associated with motivation and the emotion.
Stimulation of these neural receptors during puberty causes psychological and behavioural changes. As discussed in Chapter 9, gonadal steroid hormone receptors are primarily in
the pre-optic, and anterior hypothalamic areas and in the amgydala. Gonadal hormone stimulation of these areas influences sexual arousal, aggression, feeding, parental behaviour and emotional changes. In females, these behvioural changes are associated with changes in estrogen and progesterone levels in the menstrual cycle.

Front 124

Neuroendocrine activation at puberty: Changes in feedback regulation

Back 124

The H-P-G feedback system. In males, gonadotrophins are secreted tonically, or continuously, whereas, female secretion is cyclic. This is controlled LH-RH and FSH-RH release and the sensitivity of gonadal hormone sensitive by neurons of the median eminence, ventromedial and anterior hypothalamus, and
arcuate nucleus.

Front 125

Psychological and social changes at puberty

Back 125

Mood. First changes in puberty are probably LH-RH-LH and testosterone. May start the changes in sexual arousal. Ultrashort feedback loop - regulation of hypothalamic activity by hypothalamic releasing hormones (negative).
Males. In boys, the rise of testosterone probably causes a number of behaviour
changes including sexual arousal, and increases in aggression. Data from
monkeys shows higher increases in testosterone in dominant males than in
subordinate males - increases in sexual arousal, erections.
Females. In girls the start of menstrual cycle and estrogen/progesterone
fluctuations may cause moodiness especially if she has dysmenorrhea - not a
single menstrual period, but a random spotty bleeding over a number of weeks.
Other hormone changes.
Increases in thyroxine, TSH, production and GH also occur during puberty.
Emotional problems may relate to different rates of maturation at puberty. Conflict
of child-adult transition; self image new body and sexual arousal, change in social
roles - dating, dancing.
Adolescence - forces a new self identity and this may be altered by early or late
puberty. Many teenage problems are "outgrown". Delayed development -
inferiority. Advanced development - early adult behaviour and loss of friends.
Neurotic, anxiety symptoms may arise because of peer acceptance problems,
child-adult conflicts and social roles, e.g. teenage sex, biological adults are kept as
children by their parents.

Front 126

Activation of Sex differences in behaviour

Back 126

After puberty, sex differences in behaviour increase. Discuss. (1) sexual arousal, (2) aggression, (3) IQ scores, (4) motivation. Are these hormonal or socio-cultural?

Front 127

What determines the timing of puberty? The Gonadostat and Opiostat theories.

Back 127

(a) The gonads. The gonads are fully developed at 25 days of age. If the ovaries
of 25 day old females are implanted into adult females, they will ovulate. If testes
from 25 day old males are implanted into adult males, they will produce sperm.
If 25 day old rats are injected with FSH and LH, the males show testes growth
and testosterone secretion. Females ovulate, come into estrus mate, become
pregnant, lactate and show maternal behaviour.
The age of puberty is therefore not determined by the development of the
gonads as they function 20-30 days before puberty (in rats).
(b) The pituitary. The pituitary gland of a 25 day old rat is capable of secreting LH
and FSH if transplanted into a hypophysectomized adult rat. As early as l5 days of
age the injection of LH-FSH-RH will stimulate LH and FSH secretion.
Thus, the pituitary does not control the timing of puberty as it is functional before
puberty.
(c) Hypothalamic hormones. Does LHRH injection hasten the course of puberty?
Animal Breeders - large doses of LHRH have no effect on the timing of puberty.
[More here]
(d) Hypothalamic hormone receptors. If radioactive hormones (estrogen or
testosterone) are injected into 25 day old rats they are taken up by the appropriate
target cells in the brain. Thus, the long-loop feedback system operates before
puberty.

Front 128

The exact mechanism which "triggers" puberty is not yet understood and there may be three changes at puberty.

Back 128

(l) The secretion of FSH/LH-RH is controlled by the noradrenaline and dopamine
neurotransmitter pathways in the hypothalamus. The levels of these transmitters
are very low before puberty and reach adult levels at 35-40 days of age. Drugs
which inhibit the production of these neurotransmitters delay puberty. Thus, one
likely cause of the timing of puberty is the increased level of noradrenaline and
dopamine in the hypothalamus.
(2) Before puberty, the steroid hormone sensitive neurones of the negative
feedback loop (long loop) are very sensitive to estrogen/testosterone. The steroid
sensitive hypothalamic neurons inhibit LH-RH secretion if even tiny amounts of
gonadal steroids are detected. At puberty, the steroid sensitive neurons may
undergo an increase in firing threshold (gonadostat). Low levels of steroids are no
longer inhibitory, but higher levels are, so that LH-RH is released FSH and LH and
gonadal steroids.
(3) Finally, at puberty the pituitary may become more sensitive to LH-RH. Before
puberty there are low levels of LH and FSH

Front 129

Dual mechanism controlling puberty

Back 129

l. The hypothalamic-pituitary-gonadal negative feedback loop is the first factor that
controls puberty.
2. Because castrated (agonadal) animals show changes in LH and FSH levels
during development, changes in the negative feedback system for the gonadal
hormones cannot completely explain the timing of puberty. There must be some
intrinsic CNS neural rhythm which controls LH-RH secretion independently of
steroid feedback. Nerve cells in the brain fire a certain rhythm which influences the
timing of puberty.

Front 130

The Gonadostat Theory

Back 130

highly sensitive. Using the male as an example, if a 6 year old boy secretes some testosterone, it is picked up by neural receptors and the hypothalamic-pituitary system is very sensitive, so this testosterone causes a high amount of negative feedback, resulting in a severe inhibition of LH-RH release. Any androgens present in the circulation will shut down the LH-RH system completely. The second system, the intrinsic CNS firing system has a rhythm of cell firing in the arcuate nucleus of the hypothalamus (Figure 17.9). Before puberty, these cells fire at a low rate, releasing very little neurotrnasmitter (probably norepinephrine) As
a result of these two mechanisms, there are very low levels of LH-RH released in pulses, and LH and testosterone levels are kept very low.

Front 131

As puberty occurs, there are changes in these two mechanisms.

Back 131

During infancy and childhood, any gonadal hormone present causes
negative feedback and little LH or FSH are released. At the initiation of puberty,
this hypothalamic area is not sensitive any more and a low level of gonadal
hormone secretion is allowed. Since there is less negative feedback, more LH and
FSH are released from the pituitary. The sensitivity of the negative feedback loops
shows a gradual change and allows the gradual elevation of gonadal hormones in
the circulation, until adult levels are reached.
Simultaneously with this change in the sensitivity of the feedback loop, the cells
of the arcuate nucleus begin to fire more frequently, releasing more
neurotransmitter as the firing pulses increase. The inter-pulse-interval is about the
same before and after puberty, but the amount of neurotransmitter released at each
pulse is greatly elevated. This acts to stimulate the nocturnal pulsatile release of
LH-RH causing the 90 min surges in LH seen in puberteal girls in Figure l7.7.

Front 132

The gonadostat

Back 132

"The gonadostat" has two
parts: a feedback sensitivity and a pulse generator. The change in negative
feedback sensitivity allows the baseline levels of LH-RH and FSH-RH to increase,
while the pulse generator is responsible for the "surges" in hormone release.

Front 133

What is changing at puberty is

Back 133

(l) the sensitivity of the hormone-sensitive cells of the hypothalamus and that interacts with (2) the firing rate of the cells of the arcuate
nucleus, resulting in different levels of neurotransmitter stimulating the hypothalamic neurosecretory cells in the median eminence. Thus, the secretion of LH-RH is the essential feature of puberty. Pulsatile LH-RH release causes the pulsatile release of LH at the initiation of puberty. According to this theory, puberty is timed by the maturation of the gonadostat.

Front 134

The opioid theory

Back 134

At puberty, gonadal steroids inhibit opiate release and there are few opiate receptors, so NE release is maximal. Masculinization of opiate system perinatally alters its sensitivity or response to androgens, resulting in a masculine, continuous LH-RH secretion rather than the pulsatile female secretion. Other factors influencing the gonadostat. Figure l7.l1 shows that many other neural, hormonal,
and environmental factors can influence the gonadostat. The hypothalamus POAARC
represents the gonadostat in this Figure, and the lines show that there can be both stimulatory and inhibitory influences on this mechanism. Before puberty, neural interactions from the hippocampus can stimulate puberty, whereas, input from the amygdala and pineal gland is inhibitory. As the gonadostat matures, stimuli from the cortex and mesincephalon can influence its timing and the influences become more complex.

Front 135

Input from the cortex of CNS may mediate stress effects on the timing of puberty

Back 135

The pineal gland mediates the effects of light; the amygdala may mediate effects of odours; the hippocampus the effects of adrenal corticosteroids; and the mesencephalon and MFB- may mediate other neural stimulation (e.g. sexual arousal via tactile or visual stimulation (? is this too far fetched?)

Front 136

A number of neural, hormonal and environmental factors can modulate the
changes in the gonadostat and thus influence the timing of puberty

Back 136

High melatonin
levels, for example, appear to delay puberty (Chapter ) as do high corticosteroid
levels. Poor nutrition and low body weight can also inhibit the gonadostat while high
body weight accelerates its maturation (critical weight theory). The nutritional
factors that influence puberty may involve the level of stored body fat and thus
depend on levels of glucose, insulin, glucagon and other gastointestinal peptides
which may influence the gonadostat (has anyone tested this?)
(Blindness). Continuous light advances puberty in rats and mice by 4-7 days;
continuous darkness delays puberty by the same duration (6-8 days). This may be
mediated through the pineal gland.

Front 137

Pheromones

Back 137

Olfactory stimuli from adult animals may accelerate or inhibit puberty (primer pheromones). High population density and social stress will delay puberty. The hypothalamus controls the timing of puberty. It is affected by catecholamines (dopamine and noradrenalin); indoleamines (serotonin); pineal
secretions (melatonin and others). Benson and Migeon note a number of causes for delayed or accelerated sexual maturity in humans.

Front 138

Delayed puberty

Back 138

Can result from both low levels of gonadal steroids (hypogonadism) and low levels of gonadotrophins (hypo-gonadotrophic) or be associated with high levels of gonadotrophins (hyper-gonadotrophic). In some cases, people
with delayed puberty are given hormone treatment (FSH-LH or E/T).

Front 139

Advanced puberty

Back 139

(precocial puberty). Results from premature gonadotrophin release or from gonadal or adrenal humans, or from taking extraneous hormone treatment. Isosexual = development due to normal sex hormones. Heterosexual = development due to sex hormones of opposite sex. In advanced pubertry, there is precocious sexual development. Guiness Book - youngest mother = Linda Nadina, Peru, l939, 5 years 8 months old.

Front 140

Metabolic Activities of Androgens at Puberty

Back 140

l. Stimulates growth of penis, scrotum, seminal vesicle and prostate gland.
2. Stimulates maturation of germ cells to early spermatid stage and increases
seminiferous tubule size.
3. Promotes hair growth in pubic area, axilla, face and body. Causes scalp hair
recession.
4. Deepens voice.
5. Accelerates height growth velocity and bone maturation.
6. Increases mass of hemoglobin.
7. Increases number and size of muscle cells.
8. Thickens skin and increases sebaceous gland secretion.
9. Decreases subcutaneous fat.
l0. Promotes sex drive.
ll. Provides negative feedback on the secretion of LH-RH and LH by the
hypothalamus and pituitary.

Front 141

Metabolic Activities of Estrogen at Puberty

Back 141

A. Estrogen.
l. Increases uterine, endometrial, and vaginal growth.
2. Induces duct proliferation of the breasts.
3. Influences fat deposition and distribution.
4. Accelerates linear growth and skeletal maturation.
5. Inhibits peripheral action of growth hormone and increases growth hormone
release.
6. Increases levels of thyroxine binding globulin, cortisol binding globulin, and
testosterone-estradiol binding globulin.
7. There is a shift from negative feedback of estrogen on LH-RH to positive
feedback as estrogen stimulates LH-Rh release after puberty.

Front 142

Metabolic Activities of Progestins at Puberty

Back 142

B. Progesterone.
l. Stimulates growth and secretion of endometrial cells.
2. Densensitizes the myometrium to oxytocin.
3. Inhibits the secretory activity of the cervical glands.
4. Shifts the vaginal epithelium to an intermediate cell pattern.
5. Develops the alveolar system of the breast tissues.
6. Increases basal body temperature.
7. Provides negative feedback on the secretion of GnRH, FSH and LH.

Front 143

Chronological age

Back 143

Chronological age is how old you are, number-wise.

Front 144

Developmental (Tanner) Stage Visuals

Back 144

There are 6 tanner stages, and they correspond to level of development in males and females.

Front 145

Tanner stage males

Back 145

Tanner I

prepubertal (testicular volume less than 1.5 ml; small penis of 3 cm or less) [typically age 9 and younger]

Tanner II

testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens and enlarges; penis length unchanged [9-11]

Tanner III

testicular volume between 6 and 12 ml; scrotum enlarges further; penis begins to lengthen to about 6 cm [11-12.5]

Tanner IV

testicular volume between 12 and 20 ml; scrotum enlarges further and darkens; penis increases in length to 10 cm and circumference [12.5-14]

Tanner V

testicular volume greater than 20 ml; adult scrotum and penis of 15 cm in length [14+]

Front 146

Tanner stages females

Back 146

Tanner I

no glandular tissue: areola follows the skin contours of the chest (prepubertal) [typically age 10 and younger]

Tanner II

breast bud forms, with small area of surrounding glandular tissue; areola begins to widen [10-11.5]

Tanner III

breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with surrounding breast [11.5-13]

Tanner IV

increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast [13-15]

Tanner V

breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla.

Front 147

Tanner stages for pubic hair for both males and females

Back 147

Tanner I

no pubic hair at all (prepubertal state) [typically age 10 and younger]

Tanner II

small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora(females) [10–11.5]

Tanner III

hair becomes more coarse and curly, and begins to extend laterally [11.5–13]

Tanner IV

adult-like hair quality, extending across pubis but sparing medial thighs [13–15]|

Tanner V

hair extends to medial surface of the thighs

Front 148

Ontogenetic development

Back 148

Changes in growth and development shown in humans and animals from the time of conception to birth and throughout their lives until their death can all be viewed as "developmental changes". This life-span view focuses on ontogenetic development as a life-long process and examines the sources of behavioural variability in individuals over their life span. Because there is a high degree of
placticity or modifiability of behaviour within an individual, the course of an individual's development can take many forms, depending on their physical environment, social environment and life experiences. How ontogenetic development proceeds is also influenced by the socio-cultural conditions in which they are reared. Life-long development consists of a series of patterns of change which differ in age of onset, duration, and termination.

Front 149

Developmental changes

Back 149

Changes in growth and development shown in humans and animals from the time of conception to birth and throughout their lives until their death can all be viewed as "developmental changes".

Front 150

Lifespan Development

Back 150

Life-long development consists of a series of patterns of change which differ in age of onset, duration, and termination. Different developmental functions have different times of onset over the life-span and different temporal parametersnd that some developmental changes are
Neuroendocrinology of Development 1 - 2
1. Lifespan Development July 31, 2007
permanent while others decline after varying periods of time.

Front 151

Genetic, biochemical and socio-cultural
differences

Back 151

Because the development of each individual can be modified by a number of factors, each person or animal has the potential to develop differently if external or internal conditions are modified. Thus, genetic, biochemical and socio-cultural differences all influence the rate and level of development of an individual over
their life span. Each person or animal, therefore, has a "range of modifiability"
which defines the degree to which they can develop differently if their internal or
external environment is varied.

Front 152

Qualitative development changes

Back 152

Qualitative changes involve the onset or
offset of some process, such as reproduction, which “begins” at puberty and
“ends” at menopause in females.

Front 153

Quantitative development changes

Back 153

Quantitative changes involve the gradual growth or deterioration in the size of a body organ or the expression of a behaviour.
Thus, body weight increases from birth to adulthood and then declines in old age
and senescence. The thymus gland increases in size until puberty and then begins to decrease in size, becoming very small in old age. Behavioural development may be indicated by the age at first or last occurrence of the behaviour, in the frequency or duration of the behaviour, or in subtle differences in “quality” or intensity of the behaviour. Genetic, neurochemical and environmental factors
interact to direct the pattern of development. Thus, genetic mutations, hormonal deficiencies during the prenatal period, malnutrition during infancy, sensory deprivation during childhood and early learning experiences all may alter the
pattern of an individual’s physical, motor and/or cognitive development. Likewise,
genetic defects, hormonal abnormalities and environmental stressors may affect the
rate of reproductive decline, sensory-motor disability and cognitive dysfunction during aging.

Front 154

Longitudinal research

Back 154

A longitudinal study examines one group of subjects at different ages. Thus, one group of children would be studied at 2, 4 and 6 years of
age and the changes in each child examined. To study the effects of hormones in
development in single individuals, it is necessary to conduct longitudinal studies,
whereas studies to examine global effects of hormones on development might use
cross-sectional studies.

Front 155

Cross-sectional research

Back 155

By examining groups of individuals of different
ages in a cross-sectional study. For example, three different groups of children, ages 2 years, 4 years and 6 years old might be tested for their learning ability. This allows the comparison of groups, but does not show developmental changes in each individual.

Front 156

Measuring growth

Back 156

Growth is a complex process which involves a series of changes as well as increases, or decreases, in size. Growth may include cell
death, conversion of one material to another (eg. cartilage is converted to bone) as
well as changes in cell number and size. Cell growth and division, cell differentiation, and cell death are all components of grow.

Front 157

Molecular biology and genetics of growth

Back 157

The neurochemical basis of cell growth and development. Growth factors, neurotransmitters, neuropeptides and steroid hormones bind to specific receptors in their target cells to stimulate protein synthesis by activating nuclear regulatory proteins. The steroids bind directly to their nuclear receptors, while the growth factors, neurotransmitters and peptides bind to membrane receptors and activate second messenger systems. The proteins synthesized by the cell may be regulatory proteins such as receptors, G-proteins, enzymes, etc. which serve intracellular functions, including cell growth and development or hormones, neurotransmitters, peptides or cytokines, which are stored in secretory granules and then released.

Front 158

Measuring normal and abnormal development

Back 158

Changes in neuroendocrine, physiological and behavioural development can
be examined in each stage of development described in Table 1.1 and changes in
these features from conception to birth, from birth to maturity and from maturity
to death can be measured.
One important reason for studying developmental processes in great detail is
to detect abnormal patterns of development. Environmental factors which alter
hormone or neurotransmitter levels during "critical" periods of development can
alter one or more of the parameters of neural and behavioural organization,
depending on the time at which the manipulation occurs.

Front 159

Prenatal development - effects of teratoge

Back 159

Prenatal development involves primarily the differentiation and growth of tissues in the body and the brain. Neural and endocrine development are of particular interest in this book, but skeletal, physiological and behavioural development all begin during the prenatal period. Some behaviours, such as fetal movements can be recorded during the
prenatal stage of development (Prechtl, 1987). The ability to understand prenatal factors in development is important as these have profound effects on the development of complex behaviours such as language development in postnatal life (Largo, 1987). Much of the following chapters are concerned with prenatal factors in neuroendocrine and behavioural development.

Front 160

Teratology

Back 160

Teratology is the study of congenitally deformed fetuses and teratogens are agents which cause these deformations. Teratogens, can be hormones, drugs, environmental chemicals such as lead, polychlorinated biphenyls (PCBs), mercury, or other environmental agents, infectious diseases or radiation (Table1.6). Teratogens can alter neurochemical signals and thus alter
developmental processes. This results in changes in brain growth and in the
synthesis and release of hormones and neurotransmitters. During the embryonic period, teratogens can cause major morphological abnormalities to the developing fetus. Maternal nutrition and maternal stress can also affect fetal development.

Front 161

Some teratogens known to cause human birth defects

Back 161

Hormones
Androgens/Progesterone - Masculinization of female fetuses, ambiguous external
genitalia
Diethylstilbesterol - Abnormal uterine and vaginal development.
Drugs
Alcohol - Fetal Alcohol Syndrome, intrauterine growth retardation,
mental reatardation.
Cocaine - Intrauterine growth retardation, microcephaly,
neurobehavioural abnormalities.
Nicotine - Intrauterine growth retardation.
Thalidomide - Abnormal arm and/or leg development
Valproic acid - Craniofacial abnormalities.
Environmental Chemicals
Methylmercury - Cerebral atrophy, seizures, mental retardation.
PCBs - Intrauterine growth retardation
Infections
Cytomegalovirus - Microcephaly, sensorineural loss, delayed psychomotor
and mental development.
Human immunodeficiency - Growth failure, microcephaly, facial abnormalities
virus (HIV)
Rubella virus - Intrauterine and postnatal growth retardation, deafness,
glaucoma, mental retardation.
Toxoplasma gondii - Microencephaly, mental retardation,

Front 162

Five questions asked about critical (sensitive) periods

Back 162

1. Locus What molecular, physiological or behavioural aspect of the system has
changed as a result of a stimulus during the critical period?
2. Outcome How does the influence of experience during the critical period
manifest itself?
3. Timing When in later development does the effect of stimulation during the
critical period manifest itself relative to the onset of the critical
period?
4. Duration How long does the change induced in the critical period last, relative to
stimuli occurring after the critical period?
5. Reversibility How fixed is the change induced during the critical period, and can it
be reversed?

Front 163

Examples of circus freaks and their developmental abnormalities

Back 163

Hormonal abnormalities
Dwarfs - Growth Hormone
Giants - Growth Hormone
Abnormal genitals; hermaphrodites - sex hormones
Hirsutism; bearded lady - androgens
Other developmental abnormalities - due to genetic defects or teratogens
Obesity - extremely obese
Anorexics (Living skeletons)
Strong men
Women with 3 breasts
wild men
feral children (wolf children)
Skin diseases (Elephant man)
Conjoined twins (Siamese twins)
People with extra limbs or body parts

Front 164

The Cincinnati Developmental Test Battery for Rodents.

Back 164

Front 165

Organizational versus activational effects

Back 165

Hormones and other neurochemicals can influence whether developing cells live or die and regulate their rate of growth. Through these mechanisms, these chemical messengers modulate the developmental organization of the nervous, Neuroendocrinology of Development 1 - 13 endocrine and immune systems. Once these systems have developed fully,

chemical signals modulate their rate of activity. The interaction of the
organizational and activational effects of hormones and other neurochemicals is a
fundamental factor in the regulation of development (Tables 1.12 and 1.13). Sexual
differentiation (Chapter 6) relies on the organizational effects of gonadal hormones
and the bodily changes which occur at puberty (Chapter 12) are activated by the
gonadal hormones.

Front 166

Physical development

Back 166

- morphological measures (limb length, tooth growth, etc.).
- birth weight.
- rate of growth and weight gain.

Front 167

Reflexes

Back 167

- rooting reflex to a touch on the lips.
- Moro (startle) reflex to loud noise.
- Babinski reflex to foot tickle.

Front 168

Gross motor development

Back 168

- head and hand movement.
- sitting and standing.
- crawling, walking and climbing.

Front 169

Fine motor development

Back 169

- hand-eye co-ordination: reaching and grasping.
- thumb-finger grasping.
- picking up objects.
- using crayons, pencils, scribbling.

Front 170

Sensory development

Back 170

- orientation to visual, auditory, or olfactory stimuli.
- depth perception (visual cliff).
- attentional focus.
- responses to pain (needle prick).

Front 171

Cognitive development

Back 171

- habituation to repeated stimuli.
- conditioned suckling responses.
- visual recognition memory test.
- Bayley scale of mental development.
- Piaget's stages of mental development.
- Wechsler scales of intelligence.
- Stanford-Binet Intelligence scale.

Front 172

Language development

Back 172

- prelinguistic speech.
- Roger Brown's five stages of language development
(based on the mean length of utterances).

Front 173

Moral development

Back 173

- Kohlberg's stages of moral development.

Front 174

Social-emotional development

Back 174

- age of emergence of emotional expressions (smiling, grimacing, etc.)
- Sroufe's (1979) stages of socio-emotional development.
- Ericksen's (1950) eight stages of psychosocial development.
- Development of play behaviour.
- Development of co-operative behaviour.
- Development of aggressive behaviour.

Front 175

Sexual Development

Back 175

- Freud's stages of psychosexual development.
- Age of puberty.
- Development of gender identity and role.

Front 176

Back 176

Comparative development of blind and sighted babies. The mean age and range in ages at which sighted babies (square) and blind babies (circle) reach each development milestone is shown.

Front 177

Organizational

Back 177

A mode by which steroids affect behaviour.

- Organize neural system development during critical
periods, e.g., prenatal testosterone masculinizes females and
defeminizes them.

Front 178

Activational

Back 178

A mode by which steroids affect behaviour.

- Activate neural pathways that are already present, e.g. effect of estrogen and progesterone on female sexual behaviour.

Front 179

Two problems with this dichotomy

Back 179

1. How is this dichotomy defined and how do behavioural and
neuroanatomical data fit this dichotomy?
2. What biochemical, anatomical or physiological evidence is
there to indicate that steroids act on neurons in two different
ways?
Maybe organizational and activational effects are the result of the same
hormone action at different stages of development?

Front 180

How do organizational and activational effects differ?
5 Rules

Back 180

1. Organizational effects are permanent (irreversible); activational
effects are impermanent (short-term).
2. Organizational effects occur perinatally, around the time of birth;
activational effects occur later, usually in adulthood.
3. Organizational effects can only occur during a "critical" or sensitive
period; after which the CNS loses its plasticity. Activational effects
have no such developmental constraints, but cannot activate
behaviour until organization occurs.
4. Organization involves permanent structural changes in brain cells.
Activation involves transient modulation of neurotransmitter
production, sensitivity, etc.
5. Organizational effects are more important for masculinization than
feminization (in mammals). Activation is symmetrical with respect
to gender.

Front 181

Changes in development in adolescence and adulthood

Back 181

Biological maturity occurs at puberty with the capacity to reproduce, but social, cognitive and emotional development continue well into adulthood. The neuroendocrine changes that occur at puberty, along with a person's prenatal development and psychosocial experiences during early development shape their adult behaviour. During adolescence and adulthood, hormone levels are altered by
environmental stimuli such as light cycles, odours, temperature and stress and the
resulting neuroendocrine changes result in changes in behaviour.

Front 182

Developmental changes in old age

Back 182

As a person enters old age, they go through a number of biological, cognitive, social and personality changes. The neuroendocrine system shows a number of changes in function with age. Sensory abilities decline with age as do neuromuscular capabilities and the reproductive capacity. The menopause marks
the end of the reproductive capacity in the female whereas in aging males reproductive decline is more gradual. Some measuers of intelligence decline in old age (fluid intelligence) while others remain stable (crystallized intelligence).

Front 183

Internal and external influences on development: developmental
plasticity

Back 183

The pattern of neural development has some plasticity and can be modified by the interaction of internal (genetic, hormonal, neurochemical) and external (sensory stimuli, nutrients, experiences) stimuli. Many aspects of postnatal development involve learning by experience. The capacity to learn is thus a
developmental phenomenon which is based on neurochemical changes and synaptic plasticity in the brain. In fact, the rat fetus is able to show associative learning as early as embryonic day 17. Neuroscientists assume that synaptic plasticity underlies learning and memory, thus factors which reduce synaptic
plasticity may reduce the ability to learn and thus cause mental retardation.

Front 184

Neuroendocrinology of development

Back 184

The brain, endocrine glands, and the cells of the immune system grow like
any other organ in the body, but as they become functional, they release
neurotransmitters, neuropeptides, hormones and cytokines which regulate the growth and development of other cells. Other organs release growth factors, cell
adhesion molecules and other chemicals which target direct cell growth. These
neurochemicals bind to receptors or the surface of their target cells and activate
second messengers, such as cyclic AMP inside the target cells. This activates a
cascade of chemical reactions which regulate the permeability of the cell
membrane to ions, the synthesis and release of other chemicals and regulate the
transcription of genetic information from DNA to RNA and the synthesis of new
proteins (Brown, 1994). Thus, neurochemicals regulate cell development and the
release of other neurochemicals.

Front 185

The role of the immune system in development

Back 185

The thymus gland is essential for the maturation of T and B cells and without the thymus gland the developing organism suffers from massive infections and “wasting disease”
(Chapter 11). But what role do cytokines, the chemical messengers of the immune system, play in the neuroendocrine control of development? Are there developmental disorders that arise because of neuroimmune abnormalities, lack of cytokines or too many cytokines? Very little is known about the neuronendocrine-immune interactions in development.

Front 186

Neuroendocrine theories of aging

Back 186

Many aspects of the neuroendocrine
system change with age. Thus, it is not surprising that neuroendocrine theories of
aging propose that changes in hormones and neurotransmitters regulate the aging
process (Everitt, 1980). The sex hormones, adrenocortical hormones, cytokines and many other neurochemicals have been implicated in the aging process, which is discussed in Chapter 14.

Front 187

Some theories of Human Development

Back 187

Sigmund Freud - Psychosexual and personality development
Carl Jung - Adult development and aging
Erik Erikson - Psychosocial development
Jean Piaget - Cognitive development
John Bowlby - Attachment theory
B. F. Skinner - Development of learning: operant conditioning
Arnold Gesell - Patterns of biological maturation
J. Money & A. Ehrhardt - Neuroendocrine basis of development
Edward O. Wilson - Sociobiology of development
Albert Bandura - Cognitive and social development
L. S. Vygotsky - Cognitive development
Lawrence Kohlberg - Moral development
Noam Chomsky - Language development

Front 188

The neuroendocrine system as the mechanism of change in development

Back 188

“A unique feature of developmental theories is that they must specify some process or mechanism responsible for producing the changes that constitute development. The change mechanism constitutes a “motor” that power development. This element is crucial. How can one explain development without
identifying something that brings it about? More often than not, it sparks more discussion, debate and criticism than any other aspect of a theory, primarily for two reasons. First, it is one of the most critical features of developmental theories, and second, it is often one of the weakest components.

Front 189

Theory that biological maturation is the cause of development

Back 189

Several theories (Freud, Bowlby, Gesell and Money & Ehrhardt) posit biological maturation as the cause of development, thereby implying that individual growth is relatively fixed and mostly immune to environmental stimuli.
Accordingly, maturational theories hold that the development of such domains as personality, thinking, temperament, language, and morality is the result of an
innate plan that governs their timing and form and that cannot be altered very much by environmental events. In contrast, other theories argue that individuals are inherently malleable and flexible. Consequently, while these theories view maturation as setting broad limits on learning, they contend that it is specific environmental events that govern development.”

Front 190

Back 190

Factors affecting growth and development. Development is a process which is influenced by the complex interactions among numerous internal and external factors. Virtually all of these factors affect development through the neuroendocrine system.

Front 191

Male Reproductory System Labeled

Back 191

Front 192

The testes form part of the third order hypothalamic-pituitary-gonadal feedback system. The testes are composed of:

Back 192

(1) seminiferous tubules and (2) interstitial or Leydig cells. Spermatogenesis occurs in the Sertoli cells of the seminiferous tubule, and this is stimulated by FSH and by testosterone (acting in a pracrine fashion (?). Androgens, particularly testosterone and androstenedione and produced in these Leydig or interstitial cells and the Leydig cells are stimulated by LH or interstitial cell stimulating hormone.

Front 193

Effects of Castration

Back 193

Front 194

Feedback of testosterone on hypothalamic and pituitary hormones

Back 194

You know that in the H-P-G system, there is long-loop negative feedback of testosterone
on the hypothalamic and pituitary hormones, LH-RH and LH, and this produces a feedback
system for the regulation of LH levels. What about the other half of the system? What
regulates sperm production and FSH levels? These are regulated by a peptide hormone
produced in the Sertoli cells called Inhibin. Inhibion functions to provide negative feedback on FSH-RH and FSH (Figure 2.2). The existence of inhibition has been controversial but it is now believed to exist. Spermatogenesis or growth and development of sperm depends on FSH and testosterone stimulation. If testosterone levels are reduced, sperm production does not occur in the Sertoli
cells. Even if the male is castrated by removal of the testes, some androgens and estrogens will be secreted from the adrenal glands and this may be enough to influence some behaviours.

Front 195

Testosterone rhythms

Back 195

Androgen secretion from the testes shows a daily and an annual rhythm, with some researchers claiming a lunar or monthly rhythm (Figure 2.3). The daily rhythm of testosterone secretion shows a peak in the early morning (around 8 a.m.) and a
trough in the early evening (around 8 p.m.) in human males, thus resulting in morning
erections and increased sex arousal in the morning. The monthly cycle of male hormone
release is not very consistent (Doering et al. 1974). The annual cycle, shows a peak in
September and a trough in February and March.

Front 196

Testosterone dependent male behaviours

Back 196

There are a number of sexually dimorphic
behaviours which depend on testosterone for their activation. These include sexual behaviour,
aggression, scent-marking and odour preferences, ultrasonic-vocalizations, and inhibition of parental care (?) in some species.

Front 197

What happens when the testes is implanted or removed in roosters?

Back 197

Front 198

Back 198

The three phases of a standard hormone removal and replacement experiment. Behavioural tests are conducted one or more times during the baseline, hormone removal (post-castration) and Hormone replacement phases. A series of hormone replacement injections (arrows) is usually given during the hormone replacement phase.

Hormone removal:

surgical

pharmacological - drug (antagonist)

Immunological (antibodies)

Hormone replacement:

whole glands

purified hormones

synthetic hormones

Front 199

Constraints on hormonal activation of behaviour

Back 199

In a standard experiment on the effects of
hormones on behaviour there are three phases: baseline, hormone removal and hormone replacement (Figure 2.4). Behaviour is recorded in each phase and should covary with changes in hormone levels. When we look at the effects of hormones on behaviour, however, there are large amounts of variability in the response. These differences or cnstraints can be due to individual differences between subjects (subject variables) and differences in experimental procedures (experimental variables).

Front 200

Not all species respond the same way to gland removal (e.g. castration) and hormone
injection.

Factors that affect an animal responding differently to castration.

Back 200

The age of the animal, its past experience and learning also influence the effects of the
hormonal state. Naive, or inexperienced animals, may require more hormonal stimulation to show certain behaviours than experienced animals who may persist in "hormone-dependent" behaviour after hormone removal.
The degree of physical or psychological stress an animal is under influences its response to gonadal hormones as do the levels of other hormones and neurotransmitters, which may prime some responses and inhibit others.
The state of hunger, type of food eaten and general nutritional state (e.g. anorexic) will
also influence responses to hormone manipulation as will the use of drugs, including tobacco and alcohol.

Front 201

Back 201

When an animal or human subject is tested, the stimulus situation or manner in which
they are tested i.e. novel or familiar environment, test stimuli, etc. The type (i.e. chemical structure) of hormone used for replacement therapy, doseage level, method of hormone administration and interval between gland removal, hormone replacement and testing all influence the behavioural results. After gland removal, hormones remain in circulation for a period of time, while after hormone replacement, it takes some time for hormone levels to return to normal (Figure 2.4). This is due to up and down regulation of receptors and changes in free and bound hormones.

Front 202

Male sexual behaviour

Back 202

Sexual behaviour of male mammals involves an appetitive or

courtship phase, followed by a consummatory or copulatory phase. During the courtship

phase, there is a change in sexual arousal and in male-female interactions which may begin as

exploratory or aggressive in nature. During this period, the male is attentive to the odour,

tactile responses, and auditory stimuli from the female and may respond by scent-marking;

touching, nudging or licking the female, and producing sonic or ultrasonic vocalizations.

During the copulatory phase the male mounts the female, gains penile intromission, shows a

species typical pattern of penile thrusting and ejaculates. Males of some species mount and

ejaculate only once while others have multiple ejaculations. During the copulatory phase,

other behaviours such as aggression, olfactory investigation, scent-marking and vocalizations,

may also occur.

Front 203

Sexual arousal

Back 203

Sexual excitement causes a "burst" of LH to be discharged and this stimulates a burst of

testosterone. This may facilitate release of testosterone from Leydig cells and facilitate sexual activity. In bulls this can occur within about a half an hour. This response represents an increase in synthesis of testosterone. In mice, it has recently been shown that plasma testosterone levels increase within 30-60 min of exposure to a novel female, and does not depend on copulation (pheromones).

Front 204

Sexually experienced males castrated before puberty seldom indulge in sexual behaviour. Males castrated in adulthood show gradual decreases in sexual activity which depend on...

Back 204

...(1) the species and (2) the amount of previous sexual experience. Following castration of sexually experienced males, there are large species differences in the proportion which continue to mount and ejaculate. Notice that the decline in copulatory behaviour is gradual for all species (Figure 2.5) and that for rats, copulation is reduced almost to zero after nine weeks. Cats show a similar decline in sexual behaviour, but 20% may still copulate 15 weeks after castration. With sexually experienced rhesus monkeys, 60% still copulate 14 weeks after castration and almost all sexually experienced dogs continue to copulate. Thus, although castration inhibits sexual behaviour, there are large species differences in this and individual

differences within species. (Effects of castration on sexually inexperienced males: prepubertal castration.

Front 205

Dose dependent effects for hormone-replacement therapy.

Back 205

When hormone-replacement therapy is given after castration to rats (Figure 2.6) there is a

dose-dependent effect; so that a certain dose is required to return to pre-castration levels of

performance. Lower doses will result in partial performance. In some cases (see below) high

hormone doses result in enhanced performance.But the dose of hormone it takes to stimulate a certain behaviour is not fixed. It depends

on the time after castration, immediately versus long term castration. Hormone injection immediately after castration requires lower doses of hormone than after long term gland ablation or hormone deficiency. This is because of down-regulation of receptors.

Front 206

Methods of hormone administration

Back 206

oral administration, injections, intramuscular at i.p into the interperitoneal cavity. A third method of giving a hormone is to use a capsule implanted under the skin. A capsule gives a constant, steady release of hormone while oral release pills give slow release and injections provide "pulses" of hormone, so different methods of hormone administration will result in different types of stimulation (constant vs pulsatile). If hormones are naturally secreted in pulses, injections provide a more natural treatment and you can use "osmotic mini-pumps" which can be programmed with mini-chips to administer mini-pulses of hormone release. They are now working on these for insulin for diabetics and other hormone treatments and these can be programmed to give certain doses of hormones at certain times to provide a normal circadian rhythm of hormone release (find

data on this).

Front 207

Effects of other steroids on male sexual behaviour

Back 207

Estrogen injections also stimulate male sex behaviour in castrated adult males (Soderson, Hormones and Behavior,1973, 4, 247-256) and others. Soderson showed that adult male rats with sexual experience performed almost equally as well in sexual behaviour experiments given estrogen or testosterone, but estrogen doses had to be much larger than the testosterone doses.

Front 208

Humans have been castrated for two reasons:

Back 208

to remove testicular tumors, and, as

treatment for sex offenders. Studies of castrated sex offenders, however, show that there is a great deal of variability in response to castration. In Heim's 1981 study, 39 sex offenders were castrated between 32 and 69 years of age and they answered questionnaires given about four years after their operation. This demonstrates a number of problems with certain studies on hormones and human behaviour. First, the data depend to a great extent on introspective self reports rather than objective behavioural data; it is retrospective; and the subjects must be relied on to be truthful and to return the

questionnaires.

Front 209

Castration can cause a number of somatic and

psychological changes in males.

Back 209

These include inreased body fat, breast development (gynecomasty), osteoporosis and bone pains as well as increased "calmness", or feelings of depression and isolation.

Front 210

Heim suggests that age and personality contribute to the effects of castration on humans and suggest a number of factors which may account for these differences. These include:

Back 210

1. irritation caused by castration.

2. differences in organizational effects and their activation at puberty

3. the patient's psychological attitude to castration whether they think it should influence

their behaviour or not.

4. the stimulatory influence of adrenal androgens.

5. experience.

6. stimulus or situational factors, which enhance or inhibit sexual behaviour; i.e., marriage or

not; wife's attitude, etc.

Front 211

Are testosterone levels lower in homosexual men than in "heterosexuals"?

Back 211

In a review of six

such studies, however, Rose (19 ) found only one study where homosexuals had a lower

testosterone level, one where they had a higher level and four with no difference.

Meyer-Bahlburg (1977) reviewed much of the research on hormone levels and

homosexuality and concluded that (1) hypogonadism (undeveloped testes) seldom result in homosexual orientation, (2) most homosexual men have normal testosterone, LH and FSH levels in adulthood, and (3) female sex hormone treatment (estrogen) does not lead to a change in sexual orientation. Thus, hormone levels in adulthood do not seem to differ between homo and heterosexual males and any hormonal influence on gender identity appears to occur prenatally.

Front 212

Aggressive behaviour

Back 212

There are two types of studies to look at with respect to hormones and aggressive behaviour: correlational and experimental . A correlational study first observes the aggressive behaviour of a group of animals and ranks them from most to least

aggressive. Blood samples are then taken from each animal and analyzed for androgen levels to see if the aggressive, dominant males have a higher testosterone level than the subordinate males.

Front 213

Back 213

The effects of increasing doses of testosterone propionate on the frequency of copulations per test in male rats compared to pre-castration levels for each group.

Front 214

Correlation of testosterone levels and aggression

Back 214

In humans and primates, castration does not seem to reduce aggression. In one study,

nine of 16 men castrated for sexual offences died as the result of fighting (Kling, 19 ).

In prisoners, more violent ones were found to have higher testosterone levels and less

anxiety than less aggressive prisoners. Castration results in a reduction in fighting in rats and mice; but little change in monkeys

and dogs. In cats, Art(?) found a rapid decrease in fighting in 53%, slow decrease in 35%,

and no change in 12%. In gerbils, castration increases aggressiveness.

Front 215

Androgen replacement therapy

Back 215

Testosterone injection into castrates reinstates aggressive responses but this often depends on individual precastration aggressive levels.

Dihydrotestosterone and estrogen have been shown to increase aggressiveness in castrated

male mice.

Front 216

As shown by Yahr (19 ) with gerbils, some may become more aggressive and this depends on prior experience and on the specific stimulus situation in which it was tested...

Back 216

If the male was dominant and very aggressive before castration, he is more likely to continue to be very aggressive. If the male is tested in its own home territory, and you place an intruder in, the castrated male is just as aggressive, if not more so, than an

intact male. Thus, the stimulus situation and the effects of learning and/or experience may

counteract the effects of castration. The age at castration also influences aggressive behaviour. Males castrated before puberty are more aggressive than males castrated in

adulthood.

Front 217

Back 217

Effects of castration and daily treatment with 25 ug of testosterone on the mating behaviour of male guinea pigs that showed high, intermediate or low levels of sexual behaviour before castration. Note that when testosterone therapy was given, the individual differences seen in the baseline period returned. When mated, females given oil never fought males, but females given testosterone in

infancy showed fights 50% of the time, females given estrogen showed fights 1/3 of the time. Males given estrogen had smaller accessory sex glands thus estrogen in infancy may inhibit masculinization in intact males. Testosterone injections in females interfered with normal sexual behaviour and increased aggressiveness. This suggests that the organizing effects of testosterone in infancy are widespread and may affect many neural areas.

Front 218

Hormones and aggression in humans

Back 218

Correlational studies of androgens and aggression in humans have often used pencil and paper tests to measure aggression and these results show very low correlations with androgen levels. In correlational studies looking at hormone levels of wrestlers after winning or losing matches. Also studies of men dying in aggressive encounters. Are there any experimental studies on humans?

Front 219

Responses of fighting. Adrenocortical levels (Bronson and Elefthenieu, 1965, Science).

These authors reared mice in isolation and tested them at 85 days of age. Mice were placed in the home cage of a "trained fighter" in three groups:

Back 219

(1) fighter allowed to attack on each of

15 days; (2) fighter allowed six attacks on first five days only, (3) fighter never allowed to

attack.

Blood was collected and analyzed for corticosterone. Mice never attacked (Group three) had low corticosterone levels. Both of the exposed groups had high concentrations. This shows that in defeated mice there is a high corticosterone level. The peak occurs about one hour after exposure to the aggressive male. Subordinates were found to have heavier adrenal glands.

Front 220

Leshner has proposed a model of hormones and

aggression. In simplified form it has three components:

Back 220

(1) baseline hormone levels, (2)

stimulus processor and (3) response mechanism. (1) Baseline hormone levels. Testosterone and ACTH determine the animal's response to an intruder. High testosterone levels and low ACTH levels favor aggression or attack; low testosterone levels and high ACTH favor submission. (2) The C.N.S. response is determined by (1) neonatal hormones, (2) adult hormone levels and (3) past experience. These act to alter the shift of brain circuits to fear or aggression in novel situations. Little work has been done to test this proposition. (3) Hormonal feedback. We have seen that defeated males show increased adrenocortical activity, dominants see unaffected. Some studies have also found a depression of testosterone levels in defeated animals, and a decrease in LH. Dominant animals do not seem to show increases in testosterone or LH. Defeat appears to alter the amount of neurotransmitters in the limbic system of the brain; increasing catecholamine and serotonin levels (neurotransmitters).

Front 221

Lesher's model proposes...

Back 221

...that there is a gonadal-adrenal-neural interaction in aggression. A baseline testosterone-corticosteroid balance determines the fight-flee reaction. The

consequences of fights serve to alter the testosterone-corticosteroid balance, producing less testosterone and more C in defeated animals. This serves to alter their initial response to new situations and their odour and pheromne production.

Front 222

Scent marking

Back 222

Most mammals have scent glands on their bodies, such as the ventral gland of

the gerbil or the flank gland of the hamster, which are used for scent marking. Dogs, rats and many other mammals use urine for scent marking. Scent marking is the release of social odour or pheromones. It is also an androgendependent male behaviour. It is eliminated by castration and reinstated by testosterone injections. It probably depends on both neonatal and adrogenization and circulatory testosterone levels.

Front 223

Experiments on urine marking in male and female rats show that:

Back 223

1. males urine-mark about twice as often as females

2. castration eliminates marking in both sexes

3. testosterone increases marking in both sexes

4. estrogen increases marking, in males, not females

5. P alone does not increase marking in either sex

Front 224

Ultrasonic vocalizations

Back 224

During courtship and sexual behaviour, male rodents produce ultrasonic vocalizations. Castration reduces the number of ultrasounds and testosterone replacement increases the frequency of ultrasounds.

Front 225

Anabolic steroids and their effects on males

Back 225

The effects of anabolic steroids on muscle mass and muscle strength is a controversial topic. Anabolic actions of steroids are those that build skeletal and muscular mass and the anabolic effect of steroids, particularly synthetic androgens caus increasesd muscle mass during the growth spurt in males at puberty.

Front 226

Progesterone

Back 226

– Anti-androgenic actions

Front 227

Oxytocin/Vasopressin

Back 227

– Released during sexual behaviour (orgasm)

– Effects on smooth muscles (vas deferens)

– Effects on blood pressure (for erection)

– Neuromodulatory effects in the brain

Front 228

Stress hormones

Back 228

– ACTH/Cortisol released during stress

– Likely reduce sexual behaviour

Front 229

Haupt and Rovere (1984) have reviewed the studies on the effects of anabolic steroids and concluded that those studies in which anabolic steroids increase strength had four features:

Back 229

1. used trained weight lifters.

2. used a particular type of synthetic steroid called methandrosterolone (Dianabol)

3. test on single repetition maximal weight method

4. stay on a high protein diet

Front 230

The problem with taking these steroids are the side effects:

Back 230

both psychological and physical. The psychological side effects include a change in mood, increased aggression, and reduced sex drive. The physical side effects include gynecomostia (breast enlargement) and

endocrine side effects because the synthetic steroid provides external negative feedback to the H-P-G third-order feedback loop. The steroid, thus reduces LH-RH, FSH-RH, LH and FSH levels and thus inhibits the synthesis of testosterone in the gonads. Because the synthetic steroid does not have all of the same effects of testosterone, fertility is reduced. Figure 2.13 shows that administration of an external injection of androgen dramatically reduces sperm count. Other side effects may involve liver and circulatory system damage, but these, are controversial (Haupt and Rovere). Most of the side effects are reversible after the use of steroids is stopped and return to normal.

Front 231

Female weight lifters who take steroids...

Back 231

...usually have a disrupted menstrual cycle, voice changes, and some masculinization (e.g. Russian women's swim team: we came to swim,not to sing). Neural sites of androgenic activation of male behaviour -write about this.

Effects of testosterone metabolytes on behaviour and the aromatization hypothesis. Say a few words on this. Effects of hypothalamic and pituitary hormones in male socio-sexual behaviours. Effects of NT on male sociosexual behaviours. Effects of neuropeptides on male sociosexual behaviours.

Front 232

Sexually dimorphic behaviours

Back 232

Behaviours specific to, or shown primarily by, animals of one sex. They are often measured by how examining play behaviour and play preferences.

Front 233

Testes determining gene (SRY)

Back 233

In mammals, the Y chromosome contains the testes determining gene (SRY), which causes the bipotential gonads to develop as testes. Without a Y chromosome the gonads develop as ovaries. Fetal testosterone and adrenal androgens cause masculinization of the external genitals and the neural pathways in the brain. The external genitals determine the behaviour of other people and, as the child develops, he or she develops a self-image of their own body. Between l.5 and 4 years of age the child begins to develop a juvenile gender and role identity, including sex differences in play behaviour, toy preferences.

Front 234

Perinatal sex differences in androgen levels...

Back 234

...can result in sex differences in behaviour at very early ages. For example, very young rhesus monkeys (3.5-9 months old) show sex differences in play behaviour (Figure 13.3). Males have much higher levels of pursuit play (chasing) and rough-and-tumble play than females. Masculinized females (females given prenatal testosterone treatment) show an increase in chasing and rough and tumble play, indicating that this sex difference is mediated by prenatal hormones.

Front 235

The most important biological aspect of sexual differentiation in terms of the psycho-social environment...

Back 235

...is the sex of the external genitals. These determine how other people will behave towards a child, as a male or a female, from the moment of birth, and thus determine gender of rearing (see Table 6.1 in Chapter 6 on sexual differentaition). Parents and other adults have culturally determined expectancies about how males and females should differ and their perceptions of their newborn infants are "filtered" through these expectations.

Front 236

At puberty, the rise in gonadal hormone levels causes...

Back 236

...the development of physical, neuroendocrine and psychological changes which combine with juvenile gender identity and role to determine adult gender identity and role. All of these components interact to determine adult sexuality, which involves the hormonal activation of neural centres in the brain which cause sexual arousal and sexual motivation. Social learning and experience during development then interacts with the hormonal changes during puberty to provide a psychological interpretation of the physical changes at puberty.

Front 237

Theories in gender identity

Back 237

• Biological–Freud

– Sex

differences

in genitals

determined

iden4ty

– Stages

of

psychosexual

development

• Social

Learning-­‐

Bandura

– Differen4al

reinforcement

of

sex

typed

behaviour

– Learn

by

watching

same

sex

role

models

• Cogni4ve

Development-­‐

Kohlberg

– Gender

iden4ty

develop

along

the

same

lines

as

cogni4ve

development

(think

Piaget)

Front 238

Money and Ehrhardt's theory of gender identity and role development

Back 238

Money and Ehrhardt's (l972) combined biological-cognitive learning approach considers both the prenatal hormonal organization of behaviour and the influences of social learning on gender identity and role development (Table 13.3). According to Money and Erhardt, the development of gender identity and role depends upon "a prenatally programmed disposition coming into contact with postnatally socially programmed signals". This theory has six stages of psychosexual development which parallel those proposed by Freud.

Front 239

The prenatal stage

Back 239

Prenatal hormones "predispose" the organization of the brain to develop a male or female sex identity and role. But this predisposition requires postnatal social conditioning (see below). The perinatal surge in testosterone levels in males (Figure 13.2) is the primary hormonal event in sexual differentiation as it masculinizes the developing fetus.

Front 240

Gender dichotomy

Back 240

Gender dichotomy concerns the social expectations and socialization process by which boys and girls are treated differently. The child's external genitals determine the behaviour of the parents and other people toward the child (gender dicotomy) resulting in differences in communication with boys and girls. Parents attitudes differ towards boys and girls from the time of birth (Figure 13.4). During infancy, parents allow boys to behave more independently than girls. Sex differences are shown in play behaviour, playmates and toy preferences. Boys show more rough and tumble play and this occurs in rats, monkeys (as shown in Figure 13.3) and humans. During play behaviour children take the appropriate male or female roles, prefer to play with sex-appropriate toys and prefer playmates of the same sex. This sex difference in early play behaviour occurs long before puberty and has been attributed to perinatal androgens, but may also be influenced by social factors.

Front 241

Core gender identity

Back 241

The interaction of biological factors and parental behaviour along with the child's self-perception of his/her body leads to the development of a core gender identity. This means that deep down, the child knows they are a male or female and not the opposite sex. Once the core gender identity develops, a child will not say "My name is Jimmy and I am a boy and when I grow up I am going to be just like mommy". The child has the concept that they are male or female and this has a number of implications for their future behaviour (i.e., to be like mommy or like daddy). The child's concept of male or female roles are thus based on the behaviour of other adults; whether parents, neighbours or characters in TV shows. Core gender identity develops between l l/2 and 4 years of age.

Front 242

Gender identification and role rehersal

Back 242

Juvenile gender identity and role rehersal develop from 4-7 years of age. Once children develop a core gender identity, they develop appropriate behaviours to go with that gender identity. During gender identification and role rehersal, children learn both male and female sex roles. The sex role of their own sex is learned by identification with the same sex parent and the role of the opposite sex by complementation. Children identify with the parent of the same sex and learn the complementary role of the parent of the opposite sex.

Front 243

Consolidation

Back 243

Consolidation occurs from the age of 7 to puberty (7-l2). This is a stage of more-or-less sexual segregation, in which boys and girls maintain separate "cultures". During the stage of consolidation, the child assimilates what he/she has learned about adult sex roles and behaviour and learns how to act as an adult.

Front 244

Puberty

Back 244

Finally, during the stage of puberty, there is activation of heterosexual interest, love and sexual arousal, romantic attachment and erotic imagery.

Front 245

Transvestite

Back 245

Men who dress in the clothes of women or who feel compelled to cross-dress, often in relation to sexual arousal. There is no gender conflict. Of course, a woman may wear a suit and tie or men's work clothing without being considered a transvestite, but a man in a pink dress or nylons and high-heels is immediately so labelled. The DSM-IV-TR (2000) defines this as "Transvestic Fetishism" and considers it a "disorder described only in heterosexual males"

Front 246

Homosexuality

Back 246

This involves erotic fantasy and sexual interaction with someone of the same sex. Homosexuality can be of two types: Obligative which is compelling or exclusive homosexuality, with no heterosexual interest; and Facultative, which is optional homosexuality, which occurs in situations where no heterosexual contact is possible, such as sexually segregated schools or prisons. Often a facultative homosexual is heterosexual in other situations, or bisexual. Obligative homosexuality may be more of a gender "conflict" than facultative homosexuality.

Front 247

Bisexual

Back 247

Sexual orientation toward both males and females.

Front 248

Transsexual

Back 248

Someone who believes that they are the opposite sex and takes to living, dressing, and playing the role of the opposite sex. This is often done by people who desire to have their sex changed. They may undergo social, hormonal and surgical sex reassignment. Many are people who believe that they belong to the opposite sex and desire to have the body, appearance and social role of the opposite sex.

Front 249

Causes of gender identity and role conflicts

Back 249

According to Money and Ehrhardt (1972) and Money (1994), gender identity and role conflicts and psychosexual dysfunction can develop when there are sex errors in any of the components of the development of gender identity and role.

Front 250

Genetic bases

Back 250

Disorders involving genes on the X chromosome or the testes determining gene or other genes on the Y chromosome can lead to errors in sexual determination. These include errors of sex chromosomes (45 X0 = Turner's syndrome; 47XXY = Kleinfelter's syndrome); testes determining gene errors (SRY); errors in genes for the synthesis of glucocorticoids (congenital adrenal hyperplasia) and genes for the synthesis of androgen receptors (androgen insensitivity syndrome). Since these genetic mutations may be inherited, gender identity and role conflicts may occur in families.

Front 251

Prenatal hormone disorders

Back 251

Failure of "normal" sexual differentiation of the brain and/or external genitals may predispose a person to gender conflicts. Both neural and genital differentiation can be affected by lack of androgens or androgen receptors in males or excessive androgens in females. Hormonal disorders may also occur in males because the enzymes aromatase or 5 alpha-reductase are absent, in which case the disorder may be inherited. Teratogens may also cause neonatal hormone disorders as can maternal hormone treatment in pregnancy with androgens or progestins.

Front 252

Ambiguous external genitals

Back 252

If a child is born a hermaphrodite or pseudo-hermaphrodite, with ambiguous external genitals, this may lead to ambiguous sex assignment at birth and ambiguous gender of rearing by the parents. This can occur in syndromes which result in incomplete closure of the urogenital sinus of a male or partial closure of the vagina in a female. Incomplete development of the penis in males or enlargement of the clitoris in females may also cause ambiguity of sex assignment. Thus, genital ambiguity can occur when a female has an enlarged clitoris or a male's scrotum has failed to fuse, resulting in a vaginal-like opening. This genital ambiguity causes problems in naming the baby, in the parents "concept" of the baby (Fig. l3.2) and in ambiguous treatment of the baby in terms of early social behaviour.

Front 253

Early Socialization

Back 253

Parental encouragement of cross-dressing may be a predisposing factor for transvestism, which is defined only for males. Thus, males who are encouraged to dress as females and take on a feminine role may develop conflicts of gender identity. Parental encouragement of cross-dressing and female gender role (in boys) may include close maternal contact, reduction of aggressive behaviour, and encouragement to play with female toys (dolls). Reinforcement of children for playing with opposite sex toys or cross-dressing may facilitate gender dysphoria (Hoyenga and Hoyenga 1979). Although such explanations are compelling, there seems to be little evidence for the influence of parents on gender identity disorders.

Front 254

Poor parental sex role models

Back 254

If the child has no 'normal' sex role models from which to learn sex roles he/she may develop gender conflicts. According to Money and Ehrhardt (1972), the most difficult situation for a young child's sexual identity and role development is to have a parent who "switches roles" e.g. a transvestite father (p.l5); a domineering mother and a weak father; a bisexual mother.

Front 255

Reversed identification and complementation

Back 255

A child may identify with the parent of the opposite sex and learn the role of the same sex parent as a complementary rather than primary role. A child could, therefore, desire to grow up and take on the role of the opposite sex parent, rather than the same sex parent.

In their cross-cultural review, however, Whitam and Zent (1984) found that many homosexual and heterosexual men began cross-dressing before the age of 6, and suggested that gender identity and role reversal occured without any parental or formal influence and before the child began to identify with one parent or the other.

Front 256

Sexual segregation

Back 256

Sexual segregation during adolescent development, involving cultural injunctions against boy-girl relationships and exposure only to children of the same sex, may lead to a failure to learn complementary sex roles and a desire to be with members of the same sex due to ignorance or inexperience with members of the opposite sex (e.g. the Brtitish public school syndrome). This may give rise to facultative homosexual relationships, but not to gender identity disorders.

Front 257

Social learning at puberty

Back 257

With the populization of homosexuality as a life-style on television, gay-pride week and the gay and lesbian parade, people may choose homosexuality, transvestism or other "alternative" lifestyles as they develop their erotic interests. This may be a response to social pressure from friends, a desire for an anti-establisment lifestyle or a reaction against parental values. Many groups advertise the benefits of a homosexual lifestyle.

Front 258

Dropping out of the battle of the sexes

Back 258

Some teenagers may simply be terrified of approaching the opposite sex due to a lack of knowledge about social interactions, fear of rejection or traumatic experiences. For these people, avoiding the opposite sex may result in the formation of sexual relationships with the same sex or no sexual relationship at all.

Front 259

Andrenogenital syndrome

Back 259

Adrenogenital syndrome, or congenital adrenal hyperplasia (CAH), is the masculinization of a genetic (46XX) female by excessive androgen release from the adrenal cortex (Speiser and White 2003). The degree of masculinization can vary from very slight, in which case corrective surgery can be done and the child reared as a girl (Figure 13.6). In other cases, masculinization is complete and the child is thought to be a boy and reared as a boy (Figure 13.6) (Money and Ehrhardt 1972; Speiser and White 2003). In some cases CAH children are assigned as females at birth and reassign themselves as males later.

Front 260

Polycystic ovarian syndrome (PCOS)

Back 260

Polycystic ovarian syndrome causes infertility in up to 20% of women (Eggers and Kirchengast 2001). This disorder involves androgenization, insulin resistance, obesity, menstrual dysfunction and hirsutism (Setji et al 2007; Baldwin and Witchel 2006). The excess hair growth, lack of menstrual periods and infertility are stressful to these women, who complain of a "theft of womanhood" (Kitzinger and Willmott 2002). About half of the women seeking female-to-male sex reassignment have been found to have PCOS (Balen et al 1993; Baba et al 2007; Bosinski et al 1997). This suggests that the hyperandrogenization in PCOS women may masculinize them or that their unfeminine appearance may cause sufficient gender dysphoria for them to seek sex reassignment.

Front 261

Maternal androgen levels

Back 261

Mothers with high androgen levels may have slightly masculinized daughters. Hines et al (2002) found that maternal testosterone levels were correlated with masculinized gender role in 3.5 year old girls. Likewise women who are exposed to environmental androgens may have masculinized daughters.

Front 262

Progestins in pregnancy

Back 262

If a pregnant female takes progestins to prevent a miscarriage, these may have androgen-like properties and have a masculinizing effect on the fetus. If the fetus is female, these may increase masculinization (Table l3.8) but gender identity and sexual orientation are congruent with gender of rearing.

Front 263

Androgen insensitivity syndrome (testicular feminizing syndrome)

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Androgen insensitivity syndrome is an X-linked recessive trait in a genetic male (46XY) who lacks receptors for androgens, thus the target cells are insensitive (see Wilson 2001; Hughes 2006). There is a failure to masculinize the person's physical characteristics and they develop as feminine (Table 13.9). There is incomplete closure of the urogenital sinus and incomplete development of the penis. This results in a short vagina and an incomplete uterus, but the internal genitals (i.e., the gonads) are male - testes. Ovaries fail to develop. At puberty, breasts develop normally in response to adrenal and testicular estrogens, but there is no menarche, no menstrual cycle, and no fertility. Male secondary sex characteristics fail to develop; so there is no beard, voice change or male muscular development (Figure 13.8). As people with androgen insensitivity syndrome appear feminine, they are reared as females, and their gender identity and gender role develop as female.

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Imperato-McGinley Syndrome

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Some 46XY males have a deficiency in the enzyme 5 alpha-reductase, which converts testosterone to 5 alpha-dihydrotestosterone, or a deficiency in the enzyme 17 beta-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone (see Figure 13.7). These males have a partial failure of the external genitals to masculinize during fetal development (see Table 13.10) and the infant is assigned a female gender at birth. At puberty, however, testosterone levels increase as androgens are synthesized by different pathways (see Chapter 6 on sexual differentiation) and the child is masculinized at puberty.

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Animal models of physchosexual differentiation

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If a female rat or monkey is given perinatal injections of androgens, they can be masculinized. This is a model of andrenogenital syndrome. Similarly, if a male rat or monkey is castrated or given anti-androgenic drugs during the perinatal period, they can be feminized. This is a model of androgen insensitivity syndrome (testicular feminization syndrome) (Phoenix et al 1959;

Baum 1979). Studies with these animal models can help to understand the role of hormones and social experience on the development of sexually dimorphic behaviour and sexual orientation.

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The anti-hormone viewpoint

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Some people believe that gender identity and gender role development have nothing to do with hormones, but are due solely to "social pressure" (Rogers 1994; Ross, Rogers and Walsh 1982; McCulloch 1978) and are critical of Money and Ehrhardt's (1972) theory of the interaction between hormones and environment in the development of gender identity and role (Rogers and Walsh 1982; Rogers 1988). DeBold and Luria (1983) provide a critique of the Rogers and Walsh (1982) critique of Money's ideas. The debate is continued by Rogers (1983) and DeBold and Luria (1984).

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A biological basis for homosexuality?

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Dorner (l983) argued that there is a biological basis for homosexuality. He suggested that homosexuality was due to improper masculinization during prenatal development, possibly as a result of prenatal stress during pregnancy. He suggested that prenatal stress demasculinizes males and that a biological basis for male homosexuality could be found in the failure to masculinize the brain and hypothalamic-pituitatry-gonadal feeback system.

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Prenatal stress and homosexuality

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Dorner (l983) found that males born in Germany within a month of the big bombing raids of WWII had a higher percentage of homosexuality than males born before or after the bombing raids. In fact, the rate of homosexuality in these males was twice the average rate in Germany (Figure l3.11). Dorner argued that the prenatal stress suffered during the bombings inhibited masculinization of these males in the same way that Ward (1972) found prenatal stress caused feminization and demasculinization in male rats (see Chapter 8). Dorner's results were greeted with disdain, if not outright aggression by researchers who believed that homosexuality was a response to rearing or social-psychological influences during development. Bailey et al (1991) could not replicate Dorner's finding that homosexuality in human males was related to prenatal stresss, but these researchers did find a familial genetic link in homosexuality.

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Hypothalamic-pituitary-gonadal feedback system of homosexual males

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There are sex differences in the gonadal steroid hormone feedback mechanism. Testosterone or estrogen injections provide negative feedback on LH in normal males, causing reduced LH release, but positive feedback in females, causing an LH surge. Dorner (l983) found an LH surge in homosexual males after estrogen injection, suggesting failure of prenatal masculinization (Figure l3.12a). These suggestions were not received favorably, but a replication of Dorner's results by Gladue et al. (l984) (Figure l3.12b) has lent support to the hypothesis that in some homosexuals there has been a failure of masculinization and these males have a feminized neural development and hypothalamic-pituitary-gonadal feedback system. Gladue et al's (1984) results have also been criticized. Hendricks et al (1989) could not replicate these results nor could Gooren (1986a,b). Thus there is no final conclusion as to whether there are differences between homosexual and heterosexual men in their LH response to estrogen.

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Imperato-­‐McGinley

Syndrome

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• 46XY

• Deficiency

in

5

α-­‐reductase

OR

deficiency

in

17-­‐β

hydroxysteroid

dehydrogenase

• Assigned

female

at

birth-­‐

masculinized

at

puberty

• ‘Guevedoces’

(testes

at

12

years)

• Many

change

from

female

sexual

iden4ty

to

male!

What if there was such a disorder where 5-a reductase was not present?

46XY testes develop, yet testes develop internally, then testes become external. Testes are not as visible and not as large. They are born as male but they look like girls, and they become masculinized.

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What about homosexuality in females?

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Mustanski et al (2002) point out that much less work has been done on the biological basis of female homosexuality than on male homosexuality (Table 13.15). McFadden and Champlin (2000) and McFadden (2002) found that otoacoustic emissions and auditory evoked potentials differed between men and women. They showed that homosexual women had masculinized responses, suggesting that homosexual and bisexual females showed masculinization of the inner ear. But the same measures showed that the auditory system of homosexual males was hyper-masculinized, which is contrary to their argument of prenatal masculinization in homosexual females. Clearly these results need to be examined carefully (see Mustanski et al 2002). In studies of transsexuals, Bosinski et al (1997) found high rates of hyper-androgenic disorders in female-to-male transexuals, suggesting that these women were masculinized.

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The developmental instability theory suggests

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that some fetuses may be vulnerable to environmental and genetic stressors which cause disruptions of sexual differentiation independantly of sex hormones (see Chapter 3). These prenatal stressors could include maternal illness, infection, drug use or exposure to environmental chemicals (teratogens) such as pesticides.