Final-New Material-Rachael Flashcards
1
Q
Androgens
A
- androstenedione, DHEA, testrosterone, DHT
- Listed in order of potency
2
Q
Estrogens and Progestogens
A
- estrone, estriole, beta-estradiol (“estrogen”)
- Progesterone
3
Q
Hormone Signaling
A
- Non-polar hormones: secretion stimulated by stimulating enzymatic reactions
- Hormone bound to proteins in circulation
- Modification by enzymes in target cells
- Testosterone→dihydrotestosterone (DHT), more potent
- Enzyme: 5-alpha-reductase
- Androgens→estrogens
- Enzyme: aromatase
- Testosterone→dihydrotestosterone (DHT), more potent
- Enzymes can be drug targets
- Free hormones diffuses across plasma membrane of target cell
- Signaling via intracellular receptors that act as transcription factors
4
Q
Hormone Feedback Cycle
A
5
Q
Gametes Form by Meiosis
A
- Germ-cell: gametes and the gamete precursors
- 23 pairs of homologous chromosomes; 22 autosomes; 2 sex chromosomes
- Haploid cell has 23 single chromosomes
- In 1st division, the homologous chromosome pair up.
- Then they divide
- Crossing-over; recombination; variability
- Independent assortment; some of maternal and paternal end up dividing together
- In 2nd division, the chromatids divide up
6
Q
Nondisjunction lead to aneuploidy
A
- At first division: 2 of four have n-1, 2 of four have n+1
- At second division: 2 of four are normal, 1 n+1, 1 n-1
7
Q
Karyotype via amniocentesis or chorionic villus sampling and Cell Free DNA sampling
A
- Fetal cells: invasive: miscarriage or infection
- Placenta has fetal and maternal cells
- Branching is chorionic plate
- Protrudes into space created in endometrial spaceàmaternal blood flow
- Cell-free fetal DNA analysis:
- Small fragments of DNA enter the maternal circulation
- Early, non-invasive, blood draw
8
Q
Hormone regulation: pulsatile secretion of GnRH
A
- GnRH in the hypothalamus
- Anterior pituitary: gonadotropins
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Negative feedback regulation by gonadal steroids
- *Some positive feedback occurs in female
- Gonadotropin (FSH, LH) secretion is stimulated by pulsatile GnRH, inhibited by continuous GnRH
9
Q
Review of Pituitary Hormones
A
- 3 hormone chain of command
- Magnocellular vs. parvocellular cell
- Magnocellular release to posterior pituitary
- Parvocellular release to median eminence, delivered directly to anterior pituitary (adenhypophesis)
10
Q
Continuous Treatment with GnRH
A
- Continuous treatment with GnRH agonist (eg. Leuprolide) used to turn off reproductive function
- Precocious puberty
- Androgen deprivation therapy for prostate cancer
- Decreased secretion of testosterone
- Used in treatment of prostate cancer, endometriosis, precocious puberty
- Cycle control for IVF
11
Q
Chronology of reproductive function
A
- GnRH secretion is high during sexual differentiation, low during childhood, and high after puberty
- Sexual differentiation is before birth
- Gonadal steroid secretion during lifetime in females and males
- Females spike up and down; drops in menopause (estrogen, progesterone)
- Early menopause: look for increase FSH, would occur because of removal of negative feedback inhibition
- Males spike and then slowly decrease with age
- Females spike up and down; drops in menopause (estrogen, progesterone)
12
Q
Leptin and GnRH
A
- Leptin is part of a negative feedback loop to control adiposity
- Need leptin to allow GnRH level to increase
- The obese mutant mouse fails to make leptin and suffers from hypogonadotropic hypogonadism
- Leptin is permissive for GnRH secretion
- In abscence, no GnRH, low FSH and LH, decreased gonadal function, infertility
- Doesn’t cause start of period: other factors turning on
- At certain level of leptin, factors more likely to turn on
- Leptin, environmental estrogens
- Hypoleptinemia in women
- Low body fat, low leptin secretion, amenorrhea
13
Q
Male Reproductive Anatomy
A
- Sperm develop in seminiferous tubules→epididymis→ductus deferens (vas deferens)→ejaculatory duct→urethra
- Semen: spermatozoa plus seminal fluid
- Seminal fluid made by accessory glands:
- Bulbourethral glands: make least amount of stuff neutralizes traces of urine
- Prostate gland (1)
- Seminal vesicle (2)
14
Q
Benign Prostatic Hypertrophy (BPH)
A
- Causes urinary symptoms
- Symptoms in 1/3 men over 50
15
Q
BPH Drugs
A
-
Alpha adrenergic antagonists: Tamsulosin (Flomax)
- Relax smooth muscle in urethra
- Really specific for alpha receptors in the urethra and less likely to bind other subtypes-Not have to worry about blood pressure effects as much
-
5-alpha reductase inhibitors
- Dutasteride, finasteride
- Prostate heavily influenced by DHT
- Prevent testosterone to DHT
16
Q
Prostate Cancer
A
- Tends to be very slow growing
- Incidence and mortality of prostate cancer: effect of increased screening with PSA test
- Not specific to cancer because BPH also tests positive
- Lots of cancer diagnosis, over diagnosis
- Mortality didn’t actually go down
- Early screening has no benefit on cancer mortality rate
- Best option in most cases is to leave it alone
- Treatment increases morbidity and side effects
- Urinary, defecation, etc. can be messed up
17
Q
Spermatogenesis
A
- Differentiation from spermatid to spermatozoon
- Head of sperm:
- Nucleus
- Vesicle called the acrosome
- Contains digestive enzymes
- Important in fertilization
- Sperm made: 100 Million per day, 1000 per second
- Need 15 million sperm per mL for fertility
- Leydig cells: make testosterone
18
Q
Migration of Developing Sperm in Seminiferous Tubule (Figure)
A
19
Q
Sertoli Cells
A
- Like epithelium that wrap around and hang onto developing germ cells
- Create blood testis barrier
- Between inside of seminiferous tubule and blood
- Tight junx between sertoli cells
- Basal: spermatagonia
- Central: meiosis and mature gametes
- Isolates from immune system (central compartment)
- Nourishing/paracrine signaling required for spermtagonenisis
- Receptors for FSH and testosterone
- Produce androgen binding protein
- Endocrine cells that produce:
- Inhibin: negative feedback
- Mulllerian inhibiting substance (MIS): involved in sexual differentiation
20
Q
Sertoli Cell Functions: Summary
A
- Blood testis barrier
- Support gamete development
- Responds to FSH, testosterone
- Synthesize androgen binding protein
- Secrete hormones:
- Inhibin
- Mullerian Inhibiting Substance
21
Q
Male Hormonal Regulation
A
- Leydig cells bind to LH
- Sertoli cells bind to FSH
- Negative feedback of tropin
- Not on and off: rather fine tuning
- Muscle mass, bone growth, protein synthesis, secondary sexual structure, sex drive
22
Q
Physiology of erection
A
- 1 corpus sponginosum and 2 corpus cavernosa
- Erectile tissues that are vascular spaces that can fill up with blood and become engorged
- Relaxation of arterials and smooth muscles allows blood to flow in
- Maintenance helped because filling up compresses the veins
- neural inputs to arterial smooth muscle of the penis:
- NANC (nonadrenergic, noncholinergic) neurons:
- Releases nitric oxide as neurotransmitter
- Nitrergic neurons
- Sympathetic neurons:
- Release norepinephrine
23
Q
Erectile Dysfunction Drugs
A
- Phosphodiesterase inhibitors
- Oral drugs to treat ED
- NO stimulates guanylate cyclase
- Make cGMP
- Lead to decrease in Ca and relaxation
- PDE inactivates pathway by cleaving cGMP
- Sildenafil, vardenafil, tadalafil, avanafil
24
Q
Ejaculation
A
- Semen from urethra
- Smooth muscle contraction around the ducts
- Depends on the sympathetic input to smooth muscle
- Vas deferens + Ejaculatory Duct
- Glands
- Internal urethral sphincter
- Release of semen from penis
- Contraction of smooth muscle in urethra
- Contraction of skeletal muscles in pelvic floor
25
Q
Sexually Indifferent Stage
A
- During embryonic development
- Adjacent to each primitive gonad
- Wolffian (mesonephric) ducts are more medial
- Müllerian (paramesonephric) ducts are more lateral, but then fuse in the midline more caudally
26
Q
Sexual Determination: Male
A
- Sexual determination: depends upon the sex chromosomes, X and Y
- SRY gene on Y chromosome
- activates a gene network that directs the gonads to develop as testes
- No SRY, goes to ovaries
- Testes generate regulatory molecules
- MIS=Mullerian Inhibiting Substance
- peptide hormone
27
Q
Sexual Determination: Female
A
- Female in absence of SRY gene
28
Q
MIS Information
A
- produced in the ovary (after it differentiates) by granulosa cells
- expressed mainly by small growing follicles
- level of MIS is thus a good indicator of the size of the ovarian reserve
- Used in IVF to predict how the woman will respond to controlled ovarian stimulation
29
Q
Androgen Insensitivity Syndrome
A
- Mutation in androgen receptor
- “complete androgen insensitivity”
- Testes develop
- Externally as a female
- development of the male external genitalia depends upon androgen
- Breasts develop because testosterone converted to estrogen
- Recognized via amenorrhea
- Uterus never developed because MIS caused regression
- No armpit or pubic hair because these depend on androgen signaling
30
Q
Treatment for Androgen Insensitivity Syndrome
A
- Removal of abdominal testes
- gonadectomy
- Increased risk for testicular cancer
- Cryptorchidism (failure of testes to descend)
- Low androgen levels
- Wait until early adulthood and then gonadectomy so that naturally goes through puberty
- After gonadectomy, kept on hormone therapy
31
Q
Mutation in 5-alpha-reductase
A
- Penis and prostate development depends upon dihydrotestosterone (DHT)
- Mutation in 5-alpha-reductase type 2
- Born externally female
- Hypospadias
- Urethra not in phallus but in the perineum
- At pubery the large levles of testosterone stimulate the development of male structures
- Male secondary structures develop
- Initially raised as girls and then develop male gender identity
*
32
Q
Other Ovarin Development Signals
A
- Occurs in absence of SRY gene
- But doesn’t occur by default
- Several genes (RSPO1, WNT4, FOXL2) have been shown to be necessary to initiate ovarian development
- actively repress gene network for testes development
33
Q
Comparing Male vs. Female:
- Spermatagonia
- Spermatocyte divisions
- # of germ cells
A
34
Q
Female Oogensis Flowchart
A
35
Q
Oocytes develop into follicles
A
- Prior to birth, oogonia stop proliferating
- At birth, germ cells in ovaries are primary oocytes
- Initiated meiosis but are then in meiotic arrest
- Oocyte+support cells=follicle
- Not developing=primordial follicles
- oocyte in meiotic arrest surrounded by a single layer of follicle cells
- Once starts to develop:
- Oocyte enlarges
- Follicle cells differentiate to granulosa cells, proliferate
- Zona pellucida: glycoproteins
- Spindle shaped theca cells
- Fluid-filled antrum
36
Q
Follicle Development: Independent Development
A
- Local signals in ovary cause follicles to develop into early antral stage
- Independent of gonadotropins
- Before puberty and any time in monthly cycle
37
Q
Follicle Development: Growth Phase
A
- Follicles that have undergone initial development
- Further stimulated by rising gonadotropins (FSH) and (LH)
- If intial development not later hormonally supported, undergoes atresia
- 99.9%
- Happens all throughout childhood
- Fewer ovulations, less ovarian cancer risk
- Growing, antral follicles
38
Q
Follicle Development: Dominant Follicle
A
- Dominant follicle selected by day 7
- Day 7-14 matures
- Egg and small cluster of granulosa cells detaches from wall and follicle floats free within antrum
- Ovulation on day 14
- Follicular phase
40
Q
Hormonal Regulation: Early Follicular Phase
A
- Growth stimulated by Gn
- Decreasing estrogen and progesterone from end of cycle release the negative feedback on the anterior pituitary
- FSH=granulosa cells
- LH=theca cells
- Start secreting estrogen
- Granulosa: enzyme aromatase (makes beta estradiol)
- Theca: androgen precurosor
41
Q
Hormonal Regulation: Selection of Dominant Follicle and Late Follicular Phase
A
- Follicle enlarges and increases estrogen secretion
- Causes negative feedback inhibition
- Gn levels decline (esp. FSH)
- Granulosa secrete inhibin to prevent FSH
- Selection because negative feedback limits FSH
- Granulosa cells develop LH receptors in late follicular phase and start reponding to LH
42
Q
Hormonal Regulation: LH surge and Ovulation
A
- Estrogen from follicle cross threshold and estrogen causes postive feedback
- Causes rapid rise in LH (“surge”)
- Causes ovulation
- Just prior to ovulation, LH causes a blip of progesterone secretion (needed for ovulation)
- First division of meisosis occurs just prior to ovulation
43
Q
Hormonal Regulation: Luteal Phase
A
- LH stimulates formation of corpus luteum
- Secretes estrogen and progesterone
- Negative feedback on Gn
- Prevents further follicle development and ovulation
- LH levels fall below a threshold and corpus luteum regresses
- Release hypothalamus and pituitary from negative feedback inhibition
- FSH and LH steadliy increase to start new cycle
44
Q
Complete Diagram of Female Cycle
A
49
Q
Hyperprolactinemia: Prolactin regulation
A
- Stimulates milk production in the breast/growth
- Estrogen and progesterone prevent lactation
- Suckling stimulates mechanoreceptors
- Magnocellular Cell:
- Release oxytocin from posterior pituitary
- Milk ejections from myoepithelial cells
- Parvocellular cell that release dopamine at the median eminence
- Dopamine travel to the anterior pituitary via hypophyseal portal vessels and inhibit prolactin secretion
- Suckling inhibits dopamine release
50
Q
Hyperprolactinemia: Causes and Treatments
A
- Pituitary tumor (prolactinoma) that secretes prolactin
- Cause infertility because prolactin inhibits GnRH secretion
- Low GnRH, low FSH and LH
- Hypogonadotropic hypogonadism
- anovulation
- amenorrhea and galactorrhea
- osteoprosis
- Dopamine antagonists can cause hyperprolactima
- Gonadal hormone treatment
- First line treatment is dopamine agonist
- bromocriptine and cabergoline
52
Q
Endocrine disturbances in PCOS
A
- Normal follicle development when estrogen and progesterone levels drop due to degeneration of corpus luteum
- Granulosa respond to FSH and Theca to LH
- In PCOS, LH secretion is elevated (FSH the same or decreased)
- Theca cells and androgens produced but there is not enough FSH to stimulate granulosa cells
- Failure of follicle development to progress
- Androgen converted to estrogens in adipose tissue
- Abnormal feedback regulation
- LH continues to be high compared to FSH
- Hyperinsulinemia contributes because insulin stimulates androgen production
62
Q
Hormonal Contraceptive: MOA
A
- Suppress the secretion of gonadotropins (FSH and LH) thorugh negative feedback inhibition
- Inhibit during luteal phase
- Suppress ovulation
- Prevent rise in FSH needed for initiation of follicle development and selection of dominant follicle
- Prevents LH surge needed to trigger ovulation
- In follicular phase, estrogen makes thin water mucus that sperm can traverse
- In luteal phase, progesterone makes thick mucus. Progesterone in HC does this
- Reduce endometrial growth and interfere with implantation
- Side effect: mid-cycle bleeding from abnormal endometrial proliferation
65
Q
Emergency Contraception
A
- Block or delay ovulation since sperm can be in reproductive tract for days
- Plan B (levonorgesterol in higher dose)
- Negative feedback inhibitior of GnRH
- Only works if taken before LH surge
- Use within 12 hrs, but can be effective for 5 days
- Ella (ulipristal acetate)
- selective progesterone receptor modulator
- Blocks progesterone action in follicle
- Small increase in progesterone caused by LH surge
- Delay ovulation even if begining of LH surge has already occured
- Not effective if taken after the peak of LH surge
- May affect endometrium, but very low doses so maybe not
73
Q
Trophoblast
A
- Trophoblast is sticky and adheres to endometrium
- Promotes proliferation
- Divides into two groups
- Syncytial trophoblast: cell membrane break down, so many nuclei in one membrane
- Invasive into endometrium
- Proteolytic enzymes
- Makes chorionic gonadotropin
- Makes lacuna
- Cellular trophoblast: normal cells
- Forms chorionic villi
74
Q
Implantation
A
- Occurs 6 to 7 days after fertilization
- syncytial trophoblast
- invasisive and proteolytic enzymes
- embyro nourished by digestion of endometrium
- Digestion of endometrial tissue creates lacunae
- produce chorionic gonadotropin
- Pregnancy test
- LH analog, maintains corpus luteum
- invasisive and proteolytic enzymes
- Cellular trophobasts create branched structures, known as chorionic villi
- developing embryo forms a disc that pulls away from the proliferating trophoblast to create a new space
- amniotic cavity
79
Q
Graph of Hormonal Changes in Pregnancy
A
82
Q
Partruition: Hormonal Loop
A
- Head pushes head against the cervix
- Stretch receptors in the cervix
- Feed onto the hypothalamus
- Activate neurosecretory cells to release more oxytocin
- Positive feeback stimulation to make sure that the baby is born “all the way”
