Exam 2- Repro Flashcards
(135 cards)
1
Q
In the developing bi-potential gonad, a complex series of events are triggered by the _____
A
- sex chromosomes
2
Q
Outside the gonads, male and female is mainly dependent upon _________
A
- levels of androgen hormones
3
Q
Bi-potential organ precursors develop into ________
A
- male-specific (testosterone high)
- female-specific (testosterone low)
4
Q
What day in the developing embryo is the first surge of hormones?
A
- day 40
5
Q
Presence of the Y chromosome triggers male gonadal development how?
A
- SRY gene triggers leydig cells to secrete testosterone
- testosterone triggers sertoli cells to secrete anti-mullerian hormone which leads to regression of the mullerian ducts
- the testosterone also leads to development of male repro organs
6
Q
Testosterone and its metabolites trigger _________
A
- male-specific development in and outside the gonads
7
Q
female development is considered the default pathway and female hormones are not required until when?
A
- puberty
8
Q
Female anatomical devel occurs when?
A
- the absence of androgens
- no ledig cells and no sertoli cells lead to formation of mullerian ducts and degeneration of the wolffian ducts
9
Q
Male anatomical devel depends on what?
A
- androgen, testosterone, and its metabolites (DHT)
10
Q
Testis
A
- site of repro cells and male sex steroid production
- seminiferous tubules
- interstitial space
11
Q
seminiferous tubules
A
- found in the testes
- consists of sertoli cells and spermatogonia
12
Q
interstitial space
A
- found in the testes
- consists of leydig cells which secrete testosterone
13
Q
Ovaries
A
- site of repro cells and female sex steroid development
- consists of granulosa and thecal cells
14
Q
In what stage of follicle development does the follicle develop a thecal cell layer
A
- secondary follicles
15
Q
Are there different stages of follicles in the ovary?
A
- yes
16
Q
in a tertiary follicle which layer is the inner layer?
A
- granulosa is the inner layer, theca is the outer
17
Q
What all activates the progesterone receptor?
A
- Progesterone and a number of therapeutically synthetically altered progesterone derivs
18
Q
What all activates the androgen receptor?
A
- Androgens, DHEA, androstenedione, testosterone, DHT, others
19
Q
What all activates the estrogen receptor?
A
- Estrogens (alpha and beta), 17b- estradiol is most potent, estrone and estriol (less potent), others like environ estrogens (endocrine disrupters)
20
Q
Progestogens- what it do
A
- generally exert anti-proliferative effects on the female uterus: endometrium
- promote endometrial lining secretion rather than proliferation
- required for maintenance of pregnancy
21
Q
Androgens- what it do
A
- have masculinizing properties
- T is considered the classic circulating androgen
- DHT is the classic INTRACELLULAR androgen
- required for conversion to a male phenotype during development
- required for male sexual maturation
- required for male repro function
22
Q
Synth of androgens
A
- DHEA is a precursor to testosterone
23
Q
Testosterone
A
- major form of androgen in circulation
- must be converted into DHT in peripheral target tissues
24
Q
Testosterone action at the receptor
A
- T can bind the androgen receptor but only modest affinity and modest androgenic activity
- T is converted in target tissues to more active DHT
25
Pseudovaginal perineoscrotal hypospadias, what chromosome?
- XY chromosome
26
Estrogens- what it do
- share a common feminizing activity
- estrogens are derived from aromatization of precursor androgens
- adipose tissue is the main source of estrogen in postmenopausal women and men
27
Aromatase
- enzyme that converts precursor androgens to estrogens
- most active in the placenta and ovaries
- adipose, hypothalamic neurons, and muscle synthesizes aromatase
28
Aromatase can convert ____ to estradiol?
- testosterone
29
Testosterone to DHT to ______ to _______
- 3B-A-diol which can stim ERb receptor
30
Because the receptors of hormones are all very similar, what can happen?
- can have cross talk (different hormones binding the receptor they weren't supposed to and still activating a cascade)
31
Examples of superfamily nuclear hormone receptors
- progestogens, androgens, estrogens
32
Carrier proteins for hormone transport (2)
- sex-hormone binding globulin (SHBG)
* high affinity, low levels
- Albumin
* low affinity, high levels
33
when the hormone ligand (plus carrier protein) binds to the receptor and dimerizes, what happens next?
- recruits co-activators/co-repressors
34
Progesterone Receptor
- most progestins have significant cross-reactivity with androgen receptors
- prolonged progestin administration produces an androgenic effect
35
Synthetic progestins and receptors
- most synthetic progestins used as drugs are modified to minimize their androgenic effects
36
Androgen receptor: does whole complex translocate to the nucleus?
- yes
37
Estrogen receptor
- two types:
* classical/genomic: ERa and ERb
* membrane/non-genomic: GPR30/ERa36
- many actions of estrogens involve association of the receptor with other transcriptional cofactors
38
One way estrogens receptors increase their specificity?
- specific transcription co-factors are tissue- and ligand-dependent
- AR and PR likely share these complexities
39
Antagonists of the estrogen receptor result in what?
- selective gene transcription
| - usually results in lack of a particular gene or set of genes
40
HPG Axis overview
- hypo secretes GnRH
- travels via the hypothalamic-pituitary portal system
- stims gonadotroph cells of the anterior pituitary
- pulsatile secretion of GnRH stims gonadotropin (LH, FSH) release
41
continuous application of GnRH does what?
- suppresses gonadotroph activity
| - important pharmacological consequences in the admin of EXOGENOUS GnRH (chemical castration)
42
LH - males
- stims Leydig cells to synthesize testosterone
- T then diffuses into neighboring sertoli cells and bloodstream
- stims production of other proteins necessary for sperm maturation
43
FSH - males
- stims Sertoli cells which increases synth of androgen binding protein (ABP)
- ABP maintains high testicular [ ] of testosterone
- necessary for spermatogenesis
44
Ovaries (Pre-ovulation) - FSH
- Stims granulosa cells and increases estrogen production
45
Ovaries (Pre-ovulation) - LH
- Stims theca cells which increases production of androgens
| - androgens diffuse into neighboring granulosa cells
46
Both FSH and LH required for formation of
- estradiol
47
Ovaries (post-ovulation)
- makes estrogens and progesterone
48
HPG: feedback in males
- T produced in Leydig cell acts as a negative regulator of pituitary gland and hypo
- sertoli cells synth and secrete inhibin which works back on FSH to inhibit
- Sertoli cells also synth and secrete activin
* stims FSH release, does not affect LH release
49
HPG: feedback in females
- granulosa production of inhibins and activins
- estrogen more complex than T in men
- can involve either pos or neg feedback (depending on follicle stage)
50
Combination of estradiol and progesterone on HPG
- synergistically suppress GnRH, LH, and FSH secretion
| - actions at both the hypo and pituitary gland
51
Menstrual cycle normal range
- 24-35 days
| - "28" day model
52
Portion of menstrual cycle before ovulation (2 names)
- Follicular or proliferative phase
53
E2 (comes from where and does what)
- comes from the developing ovarian follicle
| - stims cellular prolif of the endometrium
54
Portion of menstrual cycle after ovulation (2 names)
- secretory or luteal phase
55
Corpus luteum produces which hormone and induces what in the endometrium?
- progesterone, induces endometrium to become secretory rather than proliferative
56
Ovulation: what is happening?
- estrogen levels peak at the end of the proliferative phase
- this leads to surge in LH and FSH
- results in eruption of follicle which releases the oocyte
- remaining follicle changes to lutein cells
57
Corpus luteum (what it does and processes it stimulates)
- cellular remains of the ruptured ovarian follicle
- secretes estrogen and progesterone
- endometrium begins synthesizing proteins for implantation of a fertilized egg
- blood supply to the endometrium also increases
58
First trimester of pregnancy and the endometrial glands
- secretions are very important for the fetus in first trimester
59
Uterus: proliferative phase
- follicles grow
- estrogens increase
- leads to proliferation
60
Uterus: secretory (luteal) phase
- corpus luteum produces progest and estrogen
- leads to decreased proliferation and increased secretion
- uterine secretions important for embryo
61
If fertilization and implantation do not occur within ____ days, what happens?
- within 14 days
- corpus luteum ceases production of estrogen and progesterone
- corpus luteum regresses to corpus albicans
62
Absence of estrogen and progesterone
- endometrial lining sheds and menstruation begins
- pituitary inhibition removed, FSH and LH increase
- stims the development of new ovarian follicles and another cycle
63
Fertilization and Pregnancy
- embryo secretes hCG
- corpus luteum remains viable and secretes progesterone
- production of hCG decreases after 10 to 12 weeks
- placenta begins to secrete progesterone autonomously
64
General Mechs of Repro Tract disorders for which pharmacologic agents are currently used (3)
- disruption of HPG axis
- inappropriate growth of hormone-dependent tissue
- decreased estrogen or androgen secretion
65
Disruption of HPG axis diseases (2)
- Polycystic ovarian syndrome (PCOS)
| - Prolactinoma
66
Inappropriate growth of hormone-dependent tissue (5)
- Breast cancer
- prostatic hyperplasia, prostate cancer
- endometriosis, endometrial
- hyperplasia
- leiomyomas (uterine fibroids)
67
Decreased estrogen or androgen secretion (2)
- hypogonadism
| - menopause
68
PCOS
- characterized by anovulation and increased levels of plasma ANDROGENS
- 3-5% of women of repro age
- diagnosis typically clinical (find hirsutism and anovulation)
- Multiple etiologies are likely responsible
69
LH hypoth of PCOS devel
- increase in GnRH, which increases freq and amplitude of pituitary LH pulses (90% of women with PCOS have increased circulating LH)
- Increased LH activity effects (stims thecal cells to synth increased amounts of androgens)
- increased LH and androgen levels prevent normal follicle growth
- patients with PCOS menstruate irregularly and usually very heavy
70
Insulin theory of PCOS devel
- observation that many women with PCOS are obese, insulin resistant, and secrete increased insulin
- increased insulin: decreased production of SHBG
- results in higher concentration of free testosterone
- greater androgenic effects on peripheral tissues
- insulin directly synergizes with LH to increase androgen production of thecal cells
71
Ovarian hypoth of PCOS devel
- dysreg of sex steroid synth at the level of the thecal cell
- abnormal increase in activity of oxidative enzymes for androgen synth
- greater thecal cell production of androgens in response to any given stim
72
PCOS common treatments
- Target HPG
- Target AR
- Target associated pathways
73
Target HPG for PCOS
- estrogen-progestin contraceptive to suppress LH and therefore prevent ovarian production of testosterone
- adverse: clotting, weight gain
74
Target AR for PCOS
- Spironolactone as an anti-androgen to block the masculinzing effects of T
75
Target associated pathways for PCOS
- metformin, decreases hepatic gluconeogenesis leading to decrease in insulin
- regular ovulatory menses and normalization of T levels
76
Hyperprolactinemia
- common cause of infertility among women of repro age
- clonal, benign tumors of lactotrophs in the anterior pituitary (prolactinoma)
- prolactin-secreting tumors remain responsive to inhibitory effect of dopamine agonists
77
High prolactin levels like in hyperprolactinemia results in what
- suppress GnRH release
| - causes reduction in circulating levels of LH, FSH, and estrogens
78
3 ways you can treat breast carcinoma expressing ERs
- modify hormone signalling by:
* pure antagonist
* SERM
* Aromatase Inhibitor
79
Inappropriate growth: prostate
- normal growth and maintenance requires androgens
- requires local conversion of T to DHT (stromal and basal cells of prostate)
- Treatment of BPH and metastatic prostate cancer includes androgen blockade
80
Androgen blockade for inappropriate prostate growth (3)
- 5alpha-reductase inhibitors
- receptor antagonism
- GnRH AGONIST
81
Inappropriate growth: endometriosis
- growth of endometrial tissue outside uterus
- usually found in areas surrounding fallopian tubes
- endometriosis tissues respond to estrogen stim
- grows and regresses with menstrual cycle which results in severe pain, abnormal bleeding, adhesion formation in peritoneal cavity
82
Hypoth of endometriosis origin (4)
- result from retrograde migration of endometrial tissue during menstruation
- result of metaplastic tissue growth from the peritoneum
- result of spread of endometrial cells to extra-uterine sites via lymphatic ducts
- result of increased aromatase activity in endometrial tissues
83
Endometriosis treatment
- usually estrogen dependent
- estrogen-progestin oral contraceptives
- long half-life GnRH AGONISTS
84
Hypogonadism
- impaired production of sex hormones before adolescence
- patients do not undergo sexual maturation
- hormone replacement can allow the devel of secondary sex characteristics
85
Decreased estrogen secretion: menopause
- normal physiologic response to exhaustion of the ovarian follicles
- menstrual cycles cease when all follicles are depleted from ovaries
- leads to relative lack of estrogen
86
Effects of follicle depletion in menopause
- decreased estrogen and inhibins
- results in increased LH adn FSH
- androstenedione continues to be converted to estrone
87
Effects of relative lack of estrogen in menopause
- hot flashes
- vaginal dryness
- decreased libido
- dermal atrophy
- osteoporosis
88
Post menopause: where does most estrogen come from?
- adipose tissue
89
Decreased androgen secretion: age dependent changes in men
- androgen secretion declines gradually with age
- androgen therapy in normal elderly men is controversial
- androgen replacement therapy is indicated in men with adult hypogonadism
90
as testosterone levels decrease what happens?
- muscle goes to fat... fat has more estrogen secretion
| - shift in ratios
91
Can target two major things for drugs
- HPG axis target
| - Ligand/Rc targets
92
GnRH AGONISTS
- suppress HPG axis (no longer as sensitive to GnRH in pituitary
- treats prostate cancer, some breast cancers, uterine fibroids, endometriosis, premature puberty
- prevents premature ovulation (IVF), and delays puberty for transgender
- symptoms: menopause sympt, me --> castration symptoms
- initial spike before suppression, often also given a receptor antagonist at first
93
GnRH ANTAGONISTS
- block release of FSH and LH
| - immediate action without stimulation first
94
Contraception: Combined Est and Progestin --> What does it do? (primary and secondary mechanisms)
- suppress GnRH, LH, and FSH secretion and follicular development
- Primary mech: inhibit ovulation
- most potent known way to suppress GnRH, LH, and FSH secretion
- secondary mechs: inhibit proper transport of both egg and sperm, alterations in tubal peristalsis, alterations in endometrial receptivity, alterations in cervical mucus secretions
95
Combined Est and Progestin: Rationale and Progestin actions
- Rationale: use of just estrogens causes endometrial growth which increases risk of endo cancer.. progestin administered to limit endo growth
- progestin actions: progestin receptor AGONISTS, can have some androgenic cross reactivity
96
Vaginal Ring
- cylinder packed with ethinyl estradiol and etonogestrel
- steroids released with zero-order kinetics (elim is linear)
- ring placed in vagina for 21 days, out for 7
97
Transdermal Patch
- continuous release of ethinyl estradiol and norelgestromin
- changed weekly for 3 weeks, off for 1 week
98
Oral Tablets: 21 days on, 7 days off
7 day placebo period simulates physiologic involution of corpus luteum
* causes endo to slough off leading to menstruation
* progestin inhibits endometrium proliferative growth (lighter menstruation)
* menstrual cycles often become more regular
99
Oral Tablets: 84 days on, 7 days off
- ethinyl estradiol and levonorgestrel
| - same efficacy as 21 days on, 7 days off
100
Oral Tablets: 24 days on, 4 days off
- advantage: ovulation won't occur if patient forgets to start back up after placebo
101
Formulations of the Pill
- Monophasic/constant dose (most common): same dose of estrogen and progestin for 21 days
- Biphasic: constant estrogen throughout cycle, progestin initially low and then increases during second half of cycle
- Triphasic: levels change every 7 days, increased progestin latter half of cycle, midcycle increase in estrogen dose to prevent breakthrough bleeding
- Quadphasic: Dienogest/Estradiol
102
Advantage of Biphasic or Triphasic formulation- oral contraceptives
- total amt of progestin administered over each month is reduced
- trend has been to decrease administered estrogen and progestin amounts
103
Disadvantage of multi-phase pills compared to monophasic pills
- trickier to take
| - if next pack is started late: increased risk of pregnancy
104
Any differences in adverse effects from the different phasic oral contraceptives?
- no clearly established differences
| - lowest ethinyl estradiol dose is preferred to reduce deep vein thrombosis
105
Adverse effects combined oral contraceptives
- deep vein thrombosis and pulmonary embolism
- no demonstrated increase or decrease in breast cancer
- increase in gallbladder disease (formation of gallstones)
- over 35 who smoke should not take (increased thrombotic cardiovascular events
106
Why does combined est and progest oral contraceptives increase gallbladder disease?
- estrogens can increase biliary concentration of cholesterol in bile salts
- causes increased formation of gall stones
107
Benefits of combined est and progestin oral contraceptives?
- reduces risk of endometrial cancer
| - reduces risk of ovarian cancer (lowering circulating levels of gonadotropins)
108
Progestin-Only contraception
- continuous low-dose oral progestins "mini pill"
- two progestin only contraceptives available in US
- prevents ovulation 70-80% of the time
* b/c progestins alter freq of GnRH pulsing; decrease pituitary responsiveness to GnRH
- 96-98% effective
* 2ndary mechs like alterations in cervical mucus, endometrial receptivity, tubal peristalsis
- inhibits endo prolif and promotes endo secretion
- patients taking these drugs do not typically menstruate
* breakthrough spotting and irregular, light periods common in first year
109
Progestin only contraceptive preparations (3, just list)
- Injectables
- Implants
- IUDs
110
Progestin-only contraceptives: injectables
- medroxyprogesterone acetate
- given every 3 months
- good for women who have difficulty remembering to take a pill or change a patch
111
Progestin-only contraceptives: silastic implant
- releases etonogesterel
- effective for 3 years
- implant typically inserted into dorsal side of forearm
112
Progestin-only contraceptives: IUD
- levonorgestrel
- liletta (3), skyla (3 yrs), mirena (5)
- only small amt of localized hormone reaches bloodstream
- inserted by physician
- Liletta contains same amt of progestin as Mirena and release rate about the same but only approved for 3 years
113
What kind of Birth control do breast-feeding women usually take?
- progestin-only, allows for production of breast milk
114
Emergency Contraception
- used because of failure of barrier contraceptive, recent unprotected intercourse
- Oral Levonorgestrel
* blocks LH surge disrupting normal ovulation
* produces endometrial change that prevents implantation
* dose given as soon as possible after exposure and repeated in 12 hours
- more efficacious than the ones with estrogen and progestin: fewer side effects
115
Male Contraception
- goal is to suppress endogenous production of sperm reversibly
- produce azoospermia (no sperm in ejaculate)
- difficult because even suppressing 99% leaves enough for pregnancy
- no suppression of libido or sexual functioning
- initial studies of male contraception used androgens
- admin of testosterone enanthate
* T significantly suppresses gonadotropin release
* reduced levels of LH and FSH are unable to stim sertoli cell function
116
Male contraception clinical trials
- suppression of spermatogenesis: combined androgen and progestin more completely suppresses gonadotropin release than just androgen alone
* Testosterone enanthate + daily oral levonorgestrel
* Testosterone undecanoate + Medroxyprogesterone acetate
- large population variability in degree of spermatogenesis inhibition
- on average, 60% of men because azoospermic
- significant adverse effects: acne, weight gain, potential increase in prostate size
117
Hormone Replacement Therapy: women
- perimenopausal and postmenopausal
- indications: suppress hot flashes, treat urogenital tissue atrophy (vaginal dryness)
- current recommendation: use only to treat vasomotor symptoms (hot flashes, night sweats) or vaginal dryness; use lowest possible dose for shortest amt of time
- delivery systems: Oral tablets, transdermal patches, vaginal rings
118
Women's Health Initiative: Estrogen Treatment and continuous est-progest treatment findings
- Estrogen Treatment: no increased risk of coronary heart disease or BC, decreased risk osteoporotic fracture, increased risk stroke/thromboembolism
- continuous est-progest treatment: increased risk cardiovascular, BC, and stroke, decreased osteoporotic fracture
119
Hormone Replacement: Men (Injected)
- Androgens are effective therapy for hypogonadism
- needs to be injected b/c oral is metabolized by liver in first pass
- testosterone enanthate and testosterone cyprionate
- increase plasma T to normal physiological levels
- injected IM every 2-4 weeks
120
Hormone Replacement: Men (Transdermal Patches)
- plasma testosterone remains relatively constant
- first-pass hepatic metabolism is bypassed
- adverse: skin irritation
121
Hormone Replacement: Men (Topical Gel)
- 1x/day
- plasma levels gradually increase to physiologic levels over 1 month
- can be risk of exposure if others come into contact with gel
122
Hormone Replacement: Men (Tablet)
- adheres to buccal mucosa
- results in rapid systemic absorption
- problem of compliance
123
Hormone Replacement: Men --> types of applications
- IM Injection
- Transdermal Patches
- Topical Gel
- Tablet
124
Hypogonadism in aging Men (Symptoms and recent guidelines for replacement therapy)
- Symptoms: decreased energy, libido, muscle mass, facial hair growth, gynecomastia
- recent guidelines: consistent signs and symptoms w/ low plasma T (<3 ng/ml)
- T should not be administered to men with prostate cancer
125
Abuse of androgenic/anabolic steroids
- schedule III controlled substances, illegal to use/distribute without a prescription or license
- abuse comes from ability to increase muscle mass and fat-free mass
- almost every type of androgen has been abused
- new designer androgens are harder to detect because they are metabolized quicker
126
Side effects of anabolic steroids
- CV problems including increased LDL/HDL ratio and hypertension
- Liver damage
- cancer risk increased
- male infertility
- acne
- increase in plasma estrogen resulting in gynecomastia
- mood/behavior changes
- erythrocytosis and derangements in lipid metabolism
- likely causes early mortality
127
ED causes
- hypertension
- diabetes
- CV disease
- End-stage renal disease
- nerve disorder
- psychological factors
- drugs (B-blockers, anti-androgens, estrogens)
128
What percent of men with ED suffer from low T levels?
- 8-10%
129
What is the driving force behind male sexual response?
- smooth muscle of the helicine arteries is the driving force
130
Regulation of Erection
- Norep through a-adrenergic receptor increases intracellular calcium and inhibits K channels (smooth muscle contraction)
- Prostaglandin E1 (PGE1) stims K channels and decreases intracellular Ca)
- NO stims synth of cGMP which stims K channels and decreases intracellular Ca ( smooth muscle relaxation)
131
Drugs for ED
- PDE5 inhibitors
- male sexual response is down-regulated by process that includes destruction of cGMP by PDE5
- promote penial erection by blocking destruction of cGMP in the helicine arteries
132
Female Sexual Dysfunction
- associated w/ a variety of diseases or conditions (esp est deficiency) and psychological factors
- depression
- stress
- anxiety
- hormone deficiency
- vaginal atrophy
- diminished vaginal/clitoral blood flow
133
Treatment of female sexual dysfunction w/ estrogens
- Systemic treatment (high doses est/progest)
* benefits not limited to sexual function (relief hot flashes, bone loss, improved sleep)
* risks include venous thrombosis, stroke, breast cancer
- Local/topical treatment
* vaginal estrogen cream
* vaginal estrogen ring
* vaginal tablets
134
Treatment of female sexual dysfunction with "female viagra"
- Flibanserin
- agonist at serotonin receptors, partial agonist at dopamine receptors (gets into CNS)
- FDA approved drug originally developed as anti-depressant
- treatment of premenopausal with hypoactive sexual desire disorder
- risk of serious hypotension and syncope esp in patients with hepatic dysfunction or on CYP3A4 inhibitors
135
Other approaches to treat female sexual dysfunction
- Testosterone (not FDA approved): many side effects
| - Sildenafil also not FDA approved in women
