Reproductive Physiology Flashcards
Genetic Sex
Chromosomal
Determined at fertilization
XX (homogametic, homomorphic) or XY (heterogametic) in mammals
ZZ (male) and ZW (female) in birds
Gonadal Sex
Decided by chromosomal- default is female
Testis determining genes; SRY (sex determining region of Y chromosome) and SOX9
There are also ovary-determining genes (RSPO1, WNT)- even though this is default
Phenotypic sex
What the animal looks like
Tubular and external structures
AntiMullerian Hormone, Testosterone, Dihydrotestosterone
Gonads
Initially indistinguishable (about 6 weeks in large domestic animals)
SRY
Testis Determining Factor
Synthesized in sex cord of male
Medullary sex cords differentiate into Sertoli cells; cortical sex cords degenerate (drive to male directon)
Sex cords differentiate into seminiferous tubules
Sex cords also give rise to rete testis
Male pre-sertoli cells also produce Anti Mullerian hormone
In absence of SRY cortical sex cords develop into follicles; medullary sex cords degenerate
AntiMullerian Hormone (AMH)
Secreted by Sertoli cells of fetal testis
Causes degeneration of paramesonephric (female) ducts
Absent from normal adult male
Secreted by granulosa cells of developing (antral) follicles in adult female
Amount proportional to number of developing follicles
Freemartinism
Bovine (camelids, occasionally other species)
Male and Female co-twins
Early fusion of placental circulation
-AntiMullerian hormone transferred from male to female (because of placental fusion)
-Mediates regression of paramesonephric (Mullerian) ducts
-vestigial development of vagina, cervix, uterus, uterine tubes
Almost normal vulva and vestibulum
-derived from urogenital sinus- aka not due to paramesonephric duct
Female is infertile and reproductive tract underdeveloped
Sex Reversal
Disagreement between chromosomal and gonadal sex
XX sex reversal: XX geneotype and some degree of testicular development
-XX male is bilateral testes
-xx tru hermaphrodite if testis and ovary present
Most human patients have SRY translocation to an autosomal chromosome
Hypothalamus: Male vs Female
Female hypothalamus contains two functional areas for secretion of GnRH: Tonic (arcuate ventromedial region; ARC) and Surge (preoptic area; POA) centers
Hypothalamus inherently female
-testosterone during development defeminizes the brain (T from fetal testes crosses BBB and converted to estradiol which defeminized hypothalamus, eliminating surge center
Fetal ovaries produce estradiol, but this does not cross BBB because it is bound to alpha-fetoprotein
Hormones
Signaling molecules produced in the body that regulate activity of certain cells and organs (Metabolism, sleep, lactation, growth, mood, reproduction, etc)
May be secreted by specific glands (e.g. thyroid)
Three main classes: steroid, peptides /proteins, eicosanoids
Bind specific receptors to induce response
Hormone delivery
Endocrine Neuroendocrine Paracrine Autocrine Pheromonal
Endocrine
Produced in one organ to the blood stream to find target organ elsewhere
Estradiol, FSH (pituitary to blood to testes)
Neuroendocrine
Produced and secreted by nerve cells and have direct effect on other nerve cells
GnRH (hypothalamus to pituitary)
Paracrine
From one cell and effects a neighboring cell
Testosterone from leydig cells influences Sertoli cells in testis
Autocrine
Cell produces a hormone that acts on itself
Estradiol from Sertoli cells hastens pubertal development of these cells
Pheromonal
Bruce effect, ram effects (bring ram to ewes=syncronized ovulation in all)
Supraphysiological Stimulation
Internalization of hormone receptors (face inside of cell) when overstimulated
Hormone becomes ineffective
(prolonged release, high dose GnRH as a contraceptive in dogs)
Hormone classification by structure
Peptides
Glycoproteins
Steroids
Prostaglandins
Peptides
Oxytocin, GnRH
Small molecules with few amino acids
Regulates pituitary gonadotropin secretion
Decapeptide secreted in a pulsatile manner
Both LH and FSH are secreted from the same gonadotrope cell after stimulation by GnRH
Glycoproteins
FSH, LH, TSH
Protein unit attached to carbohydrate unit. (changes half life so it degrades slower)
Alpha chain is common among hormones
Beta chain is unique for each hormone
Steroids
Estradiol, progesterone
Exactly the same between species
3 6C rings and 1 5C ring
Easily cross membrane
Prostaglandins
PGF2a, PGE2
Small fatty acid derivatives
Built out of molecules liberated from cell membrane
Huge variety- so lots of actions
Steroid biosynthesis
Cholesterol is always the starting point Needs to be transported into mitochondria for final component of steroidgenesis Then to pregnenolone To Progesterone To androstenedion (the male steroid) To estradiol and testosterone
Estradiol
Major female sex steroid
Produced mainly by follicular cells in ovary (and placenta- smaller amounts in adrenal, testis, fat, and other sites)
Two cell, two gonadotrophin synthesis
Metabolized in liver!!
Estradiol synthesis
Cholesteral -> Androstenedione (happens in theca and is stimulated by LH)
Androstenedione goes to granular cell layer and converts to estradiol with help of FSH
Estradiol Functions
Mediate sexual behavior and secondary sexual characteristics of female
Anabolic
Sexual behavior
Uterine development and function: Endometrium (cyclical fashion and estrogen dependent), Myometrium (estradiol increases myometrial activity)
Cervical Mucus (less viscose)
Increased progesterone receptors (uterus- nutrients from embryo -> anticipation of ovulation and pregnancy)
Vaginal Proliferation- tougher in anticipation of mating
Essential for mammary development
Mediates ovulatory surge of LH
Role in maintaining Pregnancy
Bone health
Estrogens
Generic term for molecules with action like estradiol
Endogenous (produced in the body): estrone, estradiol- synthesized from androgens
Exogenous (not immediately eaten up by liver): diesthystilbestrol
Progesterone
Produced mainly by ovary (specifically corpus leuteum)
CL produced after ovulation
Proliferation and differentiation of granulosa cells (large luteal cells) and theca interna cells (small luteal cells)
Both cell types produce progesterone
Metabolized by liver
Progesterone Functions
Development and function of uterus (endometrium, uterine glands)
Myometrium (quiescence-lessened activity)
Closure of cervix, increased, viscosity of cervical mucus
Maintenance of pregnancy
Development of mammary gland
Effects on brain
Effects on immune function
Progestagens
Class of hormones that bind to progesterone receptors and have progesterone-like actions
Critical for maintenance of equine pregnancy
Testosterone
Produced mainly by Interstitial Leydig cells of the testis
Metabolized mainly by liver
Testosterone Function
Masculinization
Maturation and function of male reproductive tract
Spermatogenesis
Male sexual behavior (beyond a (low) threshold)
Muscle mass, bone density
Osteoblastic
Erythripoietic
Increased BMR (less thyroid binding globulin)
Androgens
Class of compounds bind ing to androgen (testosterone) receptors
- testosterone
- dihydrotestosterone
- androstenedione
Hypothalamic-Pituitary Interrelationships
Nerves terminate in stalk and release GnRH
Anterior Pituitary releases of LH, FSH, ACTH (stimulated by GnRH from hypothalamus)
Nerve cells which release peptide hormones (oxytocin produced here)
Release of oxytocin into circulation from neurohypophysis
Hypothalamo-hypophyseal-ovarian axis
Hypothalamus
to GnRH
to FSH and LH (production of estradiol)
FSH stimulates follicular development
Estrogen-progesterone and androgen produced by ovary
These feed back negatively to the hypothalamus and anterior pituitary
Estrous Cycle Regulation
Regulated by: Pineal gland-melatonin Hypothalamus-GnRH Hypophysis-FSH and LH Ovary-estradiol, progesterone, and inhibin Uterus- prostaglandin, PF2a
Ovary
Medulla: vasculature, nerve, connective tissue
Cortex: Oocytes, follicles
Primordial Follicles
Oocyte surrounded by a single layer of squamous cells
Multiply in very early pregnancy
Arrest and number stays same- no new ones
Primary follicle
Oocyte surrounded by single layer of cuboidal cells
Activated periodically from pole- activation is a one way trip it either develops or stops
Secondary Follicle
Oocyte surrounded by two or more layers
Zona pellucida
Antral Follicle
Fluid accumulates within a cavity formed by follicular cells
Folliculogenesis
Primordial follicle: origin of oocyes, and origin of follicular (granulosa) cells Committed follicle (activated follicle from resting pool to go grow): 20-30 follicles commence to growth each day. Committed to gonadotrophin-independent growth phase Subsequent deveopment requires gonadotropin support
Most will degenerate long before they can ovulate
Oocytes penetrate early ovary and get surrounded by peripheral cells from ovary- become leydig granulosa cells
Resting Pool
Pool of inactive primordial follicles
Committed follicle
Follicle commences development from resting pool
Gonadotropin-independent growth
Follicular development up to development of antrum is independent of FSH or LH
Gn-independent
No requirement for LH and FSH
Primordial, Primary, Seconday
Gn-Responsive
Doesn’t need Gn but will be more responsive with it
Preantral
Antral
The preantral-early antral transition
Formation of the Theca cell layer
Most susceptible to follicular atresia- not developing any further
Gn-dependent
If you don’t have gonadotropin it won’t move on
Antral and preovulatory follicle
Antral follicle components
Theca externa: connective tissue
Theca interna: produce androgens under LH stimulation
Granulosa cells: produce estrogen, inhibin, and follicular fluid. Responsive to FSH
Corpus Hemorrhagicum
Structure left immediately after ovulation (after follicle)
Antrum collapses and is filled with blood
Corpus luteum
Theca interna and granulosa cells proliferate to fill the cavity, differentiate into luteal calls and produce progesterone
Large luteal cells (from granulosa; also secrete oxytocin and relaxin)
Small luteal cells (from theca interna)
Remains if pregnant
Corpus albicans
Remnant of old corpus luteum
Scar remnant
Tonic GnRH center
Frequency of GnRH pulses controlled by a pulse generator
Affected by internal and external signals
Surge center
Responsible for bursts of GnRH required to achieve preovulatory LH surge
Paraventricular nucleus
Oxytocin synthesis
Hypothalamo-pituitary portal system
Axons of hypothalamic neurons extend to blood vessels of portal system
GnRH affects anterior pituitary directly
Estrogen Function
Thickening of vaginal mucosa
Mucus secretion (cervix and cranial vagina)
Epithelial mitosis in endometrium
Increased secretory and ciliary beat activity in tubal cells
Endometrial edema
Myometrial activity
Estrous behavior
Ovulation
LH surge- precursor to ovulation
Theca interna cells produce progesterone rather than androstenedione
Collagenase (weakening follicle wall and changes to blood supply there-rupture of spot on wall)
Prostaglandins (lack of vasculature. Contractile- oocyte ejection)
CL: Progesterone
Increased endometrial secretion
Reduced myometrial activity
Priming effect in brain to enhance effects of estrogen
Luteolysis
Not pregnant, need CL to go away to have another cycle
PGF2a release from endometrium
Ipsilateral (from right uterine horn to right ovary) in ruminants
Systemic (uterus to ovary by general circulation) in mare and sow
Both systemic and counter-current in camelids (systemic in left uterine horn, local exchange in right uterine horn)
Luteolytic trigger not known in dogs (CL length is same whether pregnant or not)
Hormonal Feedback Female
GnRH in anterior pituitary. FSH and LH released and stimulate follicle growth in ovary.
Ovary released estradiol and there is a positive feedback: Graafian Follicle increases estrogen production will stimulate LH surge.
Estradiol can also stimulate inhibin and cause negative feedback to regulate FSH release.
LH can cause CL to be maintained which releases progesterone. Negative feedback will regulate the tonic release of LH to support the CL until PGF causes CL regression
Seasonality
Mediated by photoperiod
perceived by eye
melatonin produced by pineal gland during hours of darkness (synthesized from tryptophan)
Melatonin increases GnRH release in short day breeders (small ruminants)
Decreases GnRH release in long day breeders (Horses)
Puberty
The acquisition of capability of sexual reproduction Production of gametes Onset of cyclicity in females Mature sperm in males Distinguished from sexual maturity
Sexual maturity
Further body growth
Adequate size for pregnancy, delivery, lactation
Puberty mediation
No intrinsic immaturity of gonads and pituitary
Animals may be forced to ovulate by appropriate stimulation prepubertal ovaries
Hypothalamic and pituitary development
GnRH neurons originate outside brain in olfactory placode
Migrate through forebrain to hypothalamus
By midgestation the number of GnRH neurons and the Hypothalamic content of GnRH and mRNA are the same as adult
In contrast, LH and FSH content of anterior pituitary are low (as is encoding mRNA)
Juvenile pituitary unresponsive to acute dose of GnRH, but is easily upregulated by pulsatile infusion of GnRH
Pulse generator is dormant in juveniles
Neurobiologic Brake on prepubertal GnRH Pulsatility
y-amino butyric acid (GABA): negative effect of GnRH release and pulsatility
Neuropeptide Y (NPY): negative effect of GnRH release and pulsatility
Kisspeptin: positive effect on GnRH signaling. Most likely mediator of GnRH pulsatility
Leptin
Adipocyte hormone
Infusion of leptin can precipitate puberty
Leptin seems to sense somatic status: adequate body size and maturity (fat stores)
Increasing leptin may mediate onset of puberty
Preovulatory GnRH surge
Positive feedback of estradiol- enough estradiol to trigger LH surge and ovulation
Prepubertal hypothalamus exquisitely sensitive to estradiol: negative feedback on GnRH. Follicles do not develop to preovulatory size. Follicles do not produce preovulatory quantities of estradiol so surge centers are never triggered
Puberty vs Sexual Maturity
Puberty occurs at a stage when reproduction is not usually desirable
Further growth required before animal may safely and successfully undergo pregnancy, parturition and lactation
Although male animals may be capable of fertilization, maturity implies ability to be consistently fertile and impregnate an appropriate number of females
Estrous Cycle
Period from the beginning of one estrus to the beginning of the next (or from one ovulation to the next)
-follicular phase (proliferative phase in women)
-Luteal phase (secretory phase in women)
-Quiescent phase (anestrus)
Estrus is defined behaviorally
Polyestrous
Cows. Keep cycling again and again in absence of pregnancy- all year
Monestrous
Dogs. Each estrus is an individual event- lots of time (anestrus) between them