Endocrinology

Anatomy

Basics

• third ventricle

  • one of four connected fluid-filled cavities (ventricular system) within the brain

    • produces and circulate cerebrospinal fluid

      • choroid plexus produces

• sella turica

  • saddle-shaped depression in the sphenoid bone

    • diaphragma sellae (dura mater)

      • covers sella turica and pituitary gland

• diencephalon

  • interbrain

  • region of the brain that includes the thalamus, hypothalamus, epithalamus, and subthalamus

• pineal gland

  • relevant for seasonal breeders

  • melatonin and kisspeptin

  • “control over everything”

Hypothalamus

Function

• maintains homeostasis

  • influences the autonomic nervous system and manages hormones

Components

• paraventricular nucleus (PVN)

  • produces oxytocin

• supraoptic nucleus (SON)

  • produces vasopressin

    • anti-diuretic hormone

GnRH Surge Control Center

• found only in females

• contains the:

  • preoptic nucleus (PON)

  • suprachiasmatic nucleus (SCN)

  • anterior hypothalamic area (AHA)

• estrogen- positive effect

• progesterone- negative effect

  • “cap the surge”

GnRH Tonic Control Center

• found in both males and females

• contains the:

  • ventromedial nucleus (VMN)

  • arcuate nucleus (ARC)

  • median eminence (ME)

Pituitary Gland

Function

Anterior Pituitary

• adenohypophysis

  • non-neural tissue

• synthesizes:

  • Gonadatrops

    • Follicle Stimulating Hormone (FSH)

    • Luteinizing Hormone (LH)

  • Adrenocorticotropic Hormone (ACTH)

  • Growth Hormone (GH)

  • Thyroid Stimulating Hormone (TSH)

  • Prolactin (PRL)

• connected to hypothalamus via blood supply, not physically

Posterior Pituitary

• neurohypophysis

  • nerve endings stem directly from hypothalamus

• does not synthesize any hormones

  • only stores

    • oxytocin and vasopressin

    • synthesized in hypothalamus, stored in posterior pituitary

• structurally connected to hypothalamus

Neuro-Endocrine Cells’ Synthesis of Releasing Factors and Oxytocin/Vasopressin

• GnRH and oxytocin are neurohormones

  • produced in specific neural cells and released at it’s neural terminal

  • GnRH secreting neurons from the hypothalamus

    • nerves terminate in pituitary stalk (median eminence)

    • synthesized release → capillary bed

  • Oxytocin secreting neurons from the hypothalamus

    • nerves terminate in the posterior pituitary

      • release of oxytocin into circulation

  • portal vessels carry releasing hormones to anterior pituitary

    • release of LH, FSH, ACTH, PRL, GH, TSH

Blood Supply

• hypophyseal portal vessels

  • portal stalk

• superior hypophyseal artery

  • a branch from the C6 segment of the internal carotid artery

• portal vein

  • connects capillary beds

• regular vein

  • capillary bed to heart

• Key Players

  • medial hypophyseal artery (MHA)

  • primary portal plexus (PPP)

  • portal vessel (PV)

  • superior hypophyseal artery (SHA)

  • secondary portal plexus (SPP)

Hypothalamus-Pituitary Interrelationships

Hypothalamohypophyseal Portal System

• carries hypothalamic hormones specifically to the anterior pituitary in the systemic blood

  • WITHOUT dilution

• Characteristics:

  • allows rapid response

  • little dilution of peptide hormones

  • peptide hormones have a short ½ life

• specific hypothalamic nuclei secrete releasing hormones or release factors that control release of anterior pituitary hormones

  • GnRH stimulates release of LH and FSH

    • GnRH axons terminate at portal capillaries

  • preovulatory LH surge is controlled by Gonadotropin Releasing Hormone (GnRH) from the surge center

  • Tonic LH release is controlled by the tonic center

    • found in both females and males

Median Eminence

• one of three portal systems in the human body:

  • hepatic system

  • renal system

  • brain

• one of seven areas of the brain devoid of the blood-brain barrier

• unlike the general capillary system that drains blood into the heart directly through a vein

  • a portal capillary system drains blood into another capillary system through veins

• the portal system in the median eminence provides a way for the hypothalamus to communicate with the peripheral endocrine system

  • by sending and receiving signals through the portal vasculature

• site where hypothalamic releasing hormones are released into the portal capillary bed to be transported to the anterior pituitary

Magnocellular Neurosecretory Cells

• neuroendocrine neurons whose cell bodies are mainly in the:

  • paraventricular nucleus (PVN)

    • oxytocin, vasopressin

    • parvocellular neurosecretory cells

      • from the PVN and project to median eminence

      • integral to the hypophyseal portal system to anterior lobe

      • Corticotropic Releasing Hormone (CRH)

  • supraoptic nucleus

    • vasopressin

• Neurophysin-Hormone Complex

  • neurophysin

    • specific binding protein

    • transported down the unmyelinated axons of the cells to posterior lobe

• different nerve fibers have different hormone releases

• Kisspeptin

  • discovered as a metastasis inhibitor in melanoma cell lines

  • later found to be a stimulator of the reproductive system

  • genetic abnormalities involving mutation of kisspeptin:

    • cause infertility in humans

      • either lacking kisspeptin or the receptor → remain infertile

    • adolescents who lack a functioning kisspeptin system fail to achieve puberty

  • injections of synthetic kisspeptin:

    • increase levels of pituitary reproductive hormone and sex hormones

    • used to super-ovulate in human IVF procedures

Receptors

Basic Concept

• cells of target organ have specific receptors for hormones

• timing of hormone release = crucial

  • receptor may not be available if timing is not right

• for max hormone potential → 3% of receptors activated

  • 97% spare receptors

• receptor activation

  • when a receptor becomes competent to bind response elements

  • receptors exist either in the cytoplasm or nucleus

Hormones Bind to a Receptor and Stimulate a Specific Cellular Response

Specifications:

• protein and peptide hormones

  • receptor in plasma membrane

• steroid hormones

  • receptor in nucleus and plasma membrane

• prostaglandin hormones

  • receptor in plasma membrane

Response

• the number of receptors on or in a cell regulates the degree of stimulation and cellular response to the hormone

  • more sensitive = more receptors to bind

• hormones can regulate whether there is an increase or decrease in the number of receptors

Mechanisms of Steroid Hormone Action

Steroid Hormone

• not water soluble

• need a carrier protein → albumin

  • sex hormone binding to globulin

  • corticosteroid binding to globulin

  • thyroxin binding globulin

Fast Response

• seconds to minutes

• steps:

  • steroid binding to membrane receptors

  • adenylate cyclase activation

  • protein kinase activation

Slow Response

• hours to days

• Serum Response Element (SRE)

  • response elements are short sequences of DNA within a gene promotor region

    • able to bind specific transcription factors and regulate transcription of genes

Selective Estrogen Receptor Modulators

• (SERMs)

• block the action of estrogen in the breast and certain other tissues

  • by occupying estrogen receptors inside cells

• examples:

  • FSH stimulates increase in FSH receptors on granulosa cells

    • to increase:

      • estrogen synthesis

      • LH receptors

    • to prepare for ovulation

  • estrogen binds to its receptor to stimulate oxytocin receptors in myometrium

    • while progesterone blocks estrogen receptor synthesis

      • thereby removing effects of oxytocin

    • uptake estrogen → uptake oxytocin

  • lack of androgen receptor in male

    • testicular feminization

Sex Differentiation

• male (XY chromosomal pair)

  • testes determining factor (TDF) →

  • testes develop →

  • sertoli cells secrete anti-mullerian hormone (AMH)→

    • AMH regresses feminization characterisitcs

  • degeneration of paramesonephric duct

  • AMH causes leydig cells to differentiate →

    • leydig cells contain a receptor for LH to be converted to testosterone

  • testosterone and dihydrotestosterone →

    • testosterone → development of male duct system

    • dihydrotestosterone → development of penis, scrotum and accessory sex glands

  • end result = wolffian duct

• female (XX chromosomal pair)

  • no TDF →

  • ovaries develop →

  • no AMH →

  • paramesonephric ducts become: →

    • oviducts, uterus, cervix and part of vagina

  • complete female tract

  • end result = mullerian duct

Spare Receptors

• in most systems the maximum biological response is achieved at concentrations of hormone lower than required to occupy all of the receptors in/on a cell

• examples:

  • insulin stimulates maximum glucose oxidation in adipocytes

    • with only 2-3% of receptors bound

  • LH stimulates maximum testosterone production in Leydig cells

    • when 1% of receptors are bound

• maximum response with 2-3% receptor occupancy

  • 97% of receptors are “spare”

• maximum biological response is achieved when all of the “receptors” are occupied

  • average <3%

• the greater the proportion of spare receptors, the more sensitive the target cell to the hormone

  • lower concentration of hormone required to achieve half-maximal response

Hormone Box

• Gland/Hormone/Chemical Class/Principle Function(s)

  • Ovary

    • Graafian Follicle

      • Estrogen (Estradiol 17b)

        • steroid

          • female mating behavior

          • secondary sex characteristics

          • mammary growth

          • maintenance of female duct system

      • Inhibin

        • protein

          • regulates the release of FSH from the anterior pituitary

    • Corpus Luteum

      • Progesterone

        • steroid

          • maintenance of pregnancy

          • mammary growth and secretion

          • controls final follicular growth

      • relaxin (sow CL)

        • protein

          • expansion of pelvis

          • dilation of cervix at parturition

          • inhibits myometrial contractions

      • oxytocin (large luteal cells)

        • octapeptide (peptide)

          • binds to receptor on uterus

          • endometrium to release PGF2a

  • Testis

    • Leydig Cells

      • testosterone (androgen)

        • steroid

          • male mating behavior (libido)

          • spermatogenesis

          • spermatocytogenesis

          • maintenance of male duct system

    • Sertoli Cells

      • inhibin

        • protein

          • regulates the release of FSH from the anterior pituitary

  • Adrenal Cortex

    • glucocorticoids

    • cortiocosteroids

      • cortisol

        • steroid

          • induction of parturition by fetus

          • milk synthesis

          • stress response

  • Placenta

    • human chorionic gonadotropin

      • glycoprotein

        • LH-like activity

        • involved with the establishment of pregnancy in women

        • support and maintain CL

    • equine chorionic gonadotropin

      • glycoprotein

        • formation of an accessory CL

        • in equine - eCG has only LH activity

        • in non-equine, has FSH activity and some LH activity

    • estrogen/progestins

      • steroid

        • regulate placental bloodflow

        • maintenance of pregnancy

    • relaxin

      • protein

        • relaxation/dilation of cervix at parturition

    • placental lactogen

      • protein

        • stimulates mammary growth and milk secretion

  • uterus endometrium, graafian follicle, seminal vesicles