Fertility, Contraception, Gonadal Hormones & Inhibitors Flashcards
1
Q
Oxytocics Drugs:
A
Oxytocin
2
Q
Prostaglandins Drugs:
A
Dinoprostone, PGE2
Misoprostol, PGE1
Carboprost tromethamine, 15methylPGF2α
3
Q
Tocolytics Drugs:
A
Magnesium sulfate
Indomethacin
4
Q
OTC Drugs:
A
Caster Oil, Blue Cohosh, Black Cohosh, Oil of
Evening Primrose, etc.
5
Q
The myometrium is?
A
smooth muscle controlled by Calcium.
6
Q
During pregnancy- high concentrations of what hormone predominate?
A
progesterone predominates
7
Q
Progesterone causes?
A
– Hyperpolarizes uterine smooth muscle membrane
– Makes muscle non-excitable
– Prevents release of arachidonic acid aPrecursor for prostaglandins
8
Q
As parturition approaches three thinks occur?
A
– increase in estrogen to progesterone ratio.
– Increase in number of gap junctions that electrically couple myometrial muscle cells
– Increase in receptors for contractile agonists
9
Q
Clinical Use of Oxytocics
A
• Induction or augmentation of labor in case of:
• Control of postpartum uterine hemorrhage
• Induction of uterine contraction after C-section
or during uterine surgery
• Induction of therapeutic abortion
10
Q
Four reasons for Induction or augmentation of labor:
A
– Premature rupture of membranes
– Fetal growth restriction
– Uteroplacental insufficiency
– Pre-eclampsia/eclampsia
11
Q
Clinical Use of Tocolytic Agents”
A
- Delay or prevent premature parturition
- Slow or arrest delivery for brief periods for therapeutic measures including glucocorticoid therapy to increase pulmonary surfactants
12
Q
Magnesium Sulfate
Mechanism of action when given Orally :
A
laxative effect
13
Q
Magnesium Sulfate
Mechanism of action when given Parenterally
A
• As anticonvulsant - depresses the CNS and blocks peripheral neuromuscular transmissio
• To treat hypomagnesemia
• To prevent or control preeclampsia & eclampsia
– Toxemia of late pregnancy characterized by hypertension, edema and proteinuria. w/ convulsions and coma = eclampsia
14
Q
Magnesium Sulfate Pharmacokinetics:
Administered:
A
– IV administration gives immediate effect lasting 30 min
– IM administration- onset occurs in 1 hour & the duration is about 4 hours
15
Q
Magnesium Sulfate Pharmacokinetics:
Excretion:
A
Renal excretion
Mg++ reabsorbed
16
Q
Magnesium Sulfate effect on fetus & infant?
A
Crosses placenta & excreted into breast milk. No reported problems.
17
Q
The gonadotropic hormones are?
A
LH, FSH and CG because of their actions on the gonads.
18
Q
GnRH regulates systhesis & secretion of?
A
LH & FSH.
19
Q
In men, LH acts on the testicular
A
Leydig cells to stimulate synthesis of androgens, primarily testosterone, necessary for spermatogenesis.
20
Q
Dysfunction in Gonadotropic Hormones?
A
Can lead to infertility in males or females.
21
Q
Commercial pregnancy diagnostic kits depend on?
A
Qualitative detection of CG in urine of pregnant women (based on the use of antibodies specific for the unique β subunit).
22
Q
Ovulation occurs 36 hours after the onset of the?
A
LH surge, so urinary concentrations of LH (measured using LH-specific antibodies) can be used to predict the time of ovulation
23
Q
Degarelix is approved for men with?
A
advanced prostate cancer & works as GnRH Receptor Antagonists
24
Q
Goserelin, triptorelin, & leuprolide (Lupron®) are agonists of GnRH used in treatment of & work by?
A
Prostate cancer. Initially increases LH production, then decreases LH & testosterone dramatically due to receptor down regulation.
25
Histrelin nonapeptide analog of GnRH also down regulates & is used for?
Receptors. Used in treatment of precocious puberty in boys & girls.
26
Estrogen Drugs:
```
Estrogen (The natural hormones are rapidly metabolized.)
ethinyl estradiol
mestranol (ethinyl estradiol 3-methylether )
conjugated esters of estrogens
esters of estradiol
estropipate crystalline estrone sulfate
diethylstilbesterol
clorotrianisene
```
27
Progestins drugs:
1. norethindrone
2. norgestrel
3. levonorgestrel
28
Selective Estrogen Receptor Modulators Drugs:
1. tamoxifen
2. raloxifene
3. toremifene
29
Antiestrogens Drugs:
1. clomiphene
| 2. fulvestrant
30
Antiprogestins Drugs:
1. mifepristone - RU 486
| 2. onapristone
31
Aromatase inhibitors Drugs:
1. anastrozole
| 2. letrozole
32
Androgens Drugs:
The natural hormones is rapidly metabolized.
1. testosterone
2. testosterone transdermal patches
3. testosterone derivatives
4. methyltestosterone
5. testosterone propionate
6. testosterone cypionate
7. testosterone enanthate
8. fluoxymesterone
9. danazol
33
Androgen receptor antagonistsDrugs:
1. cyproterone acetate
2. flutamide
3. bicalutamide
4. nicalutamide
34
Inhibitors of 5α-Reductase Drugs:
finasteride
35
Estrogens most potent to least:
* Estradiol (the most potent & principal ovarian steroid)
* Estrone
* Estriol (least potent, principal placental steroid) also made by conversion of estradiol & estrone in liver & adipose tissue.
36
Estrogens & Androgens are bound to?
70 % bound to Sex Hormone Binding Globulin (SHBG).
37
Administration of estrogen increases?
SHBG, so free androgen level will decrease
38
Progesterone is transported?
Bound to transcortin (which also binds corticosteroids)
39
Estrogen acts through
nuclear receptors
40
Two types of estrogen receptors are? Where are they located?
ERα and ERβ
– ERα is located in the female reproductive tract (uterus, vagina and ovary) as well as many other tissues.
– ERβ is located primarily in the prostate gland & ovary.
41
Receptor/ligand complexes bind to specific regions of?
DNA & affect the rate of transcription of genes at
variable distance from the HRE (hormone response
element = DNA sequence).
42
Many steroid hormones weakly?
Cross-react with receptors for other steroid hormones.
43
Progesterone may have weak?
Androgenic & glucocorticoid effects.
44
Most steroid hormones affect the synthesis?
Of their own receptors.
45
Antihormone action is achieved by?
Competitive binding of ligands (antagonists) to the receptor. Such a ligand-receptor complex may still bind to the DNA, but exert no effect.
46
Actions of Estrogens Coordinate the systemic responses?
During the menstrual cycle
– Reproductive tract
– Pituitary gland
– Breasts and other tissues
47
Actions of Estrogens in the body?
• Increases HDL and lowers LDL cholesterol.
• Breast development
• Hastens bone maturation & closure of epiphyseal
plates of long bones.
• Antagonizes bone resorption
• Shapes pelvis (larger opening for birth)
• Increases muscle content of the myometrium
• Increases libido
• Increases synthesis of several hepatic proteins: TBG, transcortin, SHBG & clotting factors.
48
The major effect of estrogen on bone is to?
Decrease the numbers and activity of osteoclasts.
49
Progesterone is a precursor to?
Estrogens, androgens & adrenocortical steroids
50
Progesterone is synthesized in the?
Ovary, adrenal gland & testis. Released in large amounts by the placenta during pregnancy.
51
Actions of Progesterone:
• Responsible for the alveolobular development
of the secretory apparatus in the breast
• Modulates estrogen action on the uterus
• Aids in the maintenance of pregnancy
• Inhibits uterine contraction
52
Actions of Progesterones on metabolism:
• Alters carbohydrate metabolism (increases
basal insulin levels, promotes glycogen
storage)
• Decreases HDL levels and stimulates LDL
production
• Stimulates lipoprotein lipase (fat transfer from
lipoproteins to tissues)
• Responsible for body temperature increase at
ovulation
• May have depressant and hypnotic effects on
the brain.
53
Native estrogens are rapidly degraded by & making them not useful for?
The liver (high first-pass effect). Not effective given orally in treament or replacement therapy.
54
Synthetic estrogens such as?
| Have ethinyl groups (triple bonds) which greatly?
ethinyl estradiol & mestranol
| decrease hepatic metabolism.
55
Ethinyl estradiol & mestranol are often used?
In oral contraceptives. Similar alterations are also effective in progestin preparations.
56
Synthetic nonsteroidal estrogens such as DES
(diethylstilbesterol) & clorotrianisene have also been
used in?
Prostate cancer therapy & birth control.
57
Nonsteroidal estrogens such as DES (diethylstilbesterol) & clorotrianisene (replaced once or twice weekly) have been used to avoid?
The first pass effect.
58
Intramuscular injections of sulfate esters of estrone from equine sources or esters of estradiol dissolved in oil are absorbed over several weeks time and also avoid?
The first pass effect.
59
Sulfate esters of estrone from equine sources or esters of estradiol used to treat?
Symptoms of menopause in women with hysterectomy (also HRT).
60
SERMS ( Selective Estrogen Receptor Modulators ) are drugs whose estrogenic activities are?
tissue selective.
61
SERMS produce estrogenic activities in tissues some tissues & no activity in others?
They are beneficial (bone, brain and liver), but have no activity or antagonistic activity in breast or
endometrium.
62
SERMS Examples are?
tamoxifen, raloxifene, and
| torimifene.
63
Tamoxifen has been reclassified?
no longer considered an antiestrogen.
64
SERMs are used in?
breast cancer treatment because they block estrogen stimulation of the cancer growth, but have normal effects elsewhere.
65
The true antiestrogen is?
clomiphene are pure antagonists in all tissues. It is used as an ovulation inducing agent.
66
Therapeutics - Estrogen and Progesterone
| Fertility control:
– Combination of estrogen & progestin for contraception
– Progestin only pill for contraception
– Postcoital contraception (morning after pill)
– Contragestation (antiprogestin - mifepristone - RU 486)
67
Therapeutics - Estrogen and Progesterone
| Hormone Replacement Therapy
– Menopause (mostly estrogens)
– Osteoperosis in menopause or in young women after ovariectomy (estrogens)
– Ovarian failure (estrogens & progestins)
68
Therapeutics - Estrogen and Progesterone
| Dysfunctional uterine bleeding:
Irregular menstrual cycle (progestins, estrogens)
69
Ovulation induction for infertility in an ovulatory
| women what drugs used?
clomiphene & fulvestrant
70
Clomiphene & fulvestrant are antiestrogens, pure
| antagonists in?
All tissues, bind to both ERα and ERβ.
71
Clomiphene & fulvestrantact on the ER in the hypothalamu to/
Block feedback inhibition of natural estrogens, & stimulate release of GnRH which stimulates the pituitary to increase LH and FSH secretion leading to ovulation. (This results in increased estrogen levels, also.)
72
Aromatase inhibitors are used for?
2. Progestins and antiestrogens used in treatment of
Endometrial cancer.
3. Estrogens used in treatment of prostate cancer.
breast cancer (anastrozole & letrozole) used after tamoxifen failure.
73
Aanastrozole & letrozole decrease?
Estrogen to extremely low levels after estrogen levels are lowered by hysterectomy. Inhibit conversion of adrenal androgens to estrogens.
74
Long known (1936) that administration of estrogen to several mammalian species will?
Produce tumors of breast, uterus, testis, bone, kidney and other tissues (high dose).
75
Developmental exposure to some estrogens (especially DES) causes?
tumors in the fetus.
76
Some risk of endometrial cancer with estrogen alone used for?
HRT in menopause.
77
Recent studies indicate that the progestin component may play a role in?
cancer risk in HRT.
78
Difficult to assess the problem because of high incidence of?
breast cancer in women without known risk factors. 50% of women who develop breast cancer have no known risk factors other than gender & age.
79
Cardiovascular problems with Estrogens & Progestins:
• Estrogens decrease risk of CHD, progestins raise
the risk.
• Estrogens increase the risk of stroke by increasing the chance of venous thromboembolism.
• Even more elevated risk for women who smoke.
80
Additional clinical problems with estrogens include:
- GI disturbances
- menstrual disorders
- breast discomfort
- hypertension
- endometrial cancer
- decreased lactation
- adverse effects on the fetus (DES)
81
Additional clinical problems with progestins include:
- GI disturbances
- menstrual disorders
- adverse changes in lipoprotein levels
82
Contraception most effective:
IUDs, progestin implants & sterilization are most effective.
83
Contraception least effective:
Barrier and fertility-based methods (calendar) are least effective.
84
Contraception most popular:
Hormonal contraceptive are most popular
85
Birth Control Combination of Estrogen/Progestin Mechanism?
Prevents LH & FSH release by feedback inhibition
86
Birth Control Combination of Estrogen/Progestin Component drugs?
• Estrogen component is ethinyl estradiol or mestranol
• Synthetic progestin component is norethindrone,
norgestrel or levonorgestrel
87
Birth Control Combination of Estrogen/Progestin Component side effects?
• Estrogen component is responsible for breast enlargement, increased excitability
• Progestin component is responsible for acne & weight gain
• Formulations of various combinations are available
to minimize side effects.
88
Contraindications for Combination Oral Contraceptives Include?
* Thromboembolic disease
* Cerebral vascular disease
* Myocardial infarction
* Coronary artery disease
* Congenital hyperlipidemia
* Known or suspected breast cancer
* Endometrial cancer
89
Single component type Contraceptives such as low dose of progestin success rate?
Blocks ovulation in only 60 to 80 % of cycles. Impairs sperm transport by thickening the
cervical mucus, decreases motility of ovules in
the oviduct & alters endometrium to impair
implantation. Minipill has a slightly higher failure rate than the combination pill.
90
ORAL CONTRACEPTIVES have decreased over the
| years?
Hormone content. Lower dose formulations (<20 mcg of ethinyl estradiol) are effective, but have higher risk of failure and changes in bleeding patterns (irregular, frequent or prolonged)
91
Monophasic oral contraceptives have?
Fixed doses of estrogen & progestin in each
| active pill
92
Multiphasic oral contraceptives vary the?
Dose of one or both hormones (but no evidence of decreased adverse effects)
93
Most oral contraceptive packaged as/
21/7 cycle (21 active/7 placebo)
| –Results in 13 bleeding episodes per year
94
Some newer oral contraceptive regimens have?
2-4 placebo tablets per 28 days
95
One new oral contraceptive regimen has
No placebo tablets (28 identical active pills)
96
Women taking combination oral contraceptives
| have reduced risk of?
Ovarian & endometrial cancer (after 1 yr & continues)
97
Non-Contraceptive Benefits reduced dysfunctional?
Uterine bleeding & dysmenorrhea
98
Non-Contraceptive Benefits Menstrual regularity leads to?
Increased hemoglobin.
99
Non-Contraceptive Benefits Combination pills raise?
SHBG, decrease androgens, so less hirsuitism & acne
100
Combination Contraceptive pills used "off-label" to treat?
poly cystic ovary syndrome
101
Adverse Effects of Oral Contraceptives Include:
• Estrogens cause nausea, breast tenderness,
breast enlargement
• Lower dose of ethinyl estradiol have more breakthrough bleeding
• Unexpected bleeding common with extended cycle (24/4) or continuous regimen (no placebo)
• Older formulations with >50 mcg of ethinyl estradiol caused more MI and stroke
• Venous thromboembolism with combination pills, especially in smokers
102
Progesterone-only "Mini-pill" taken?
* Taken daily and continuously. No placebo.
| * Take pills at the same time each day
103
Progesterone-only "Mini-pill" best for?
* Best for women who are breast-feeding
| * For women >35 years old who smoke
104
Contraceptive failure reported in women
| taking?
Antibiotics, including penicillins & tetracyclines (cause not established)
105
Rifampin, some anti-HIV agents, anticonvulsants, and St. John's wort effect on Oral Contraceptives?
Increase hormone metabolism & decrease
| effectiveness
106
Hormonal Contraceptives: Transdermal Patch Delivers & administered?
• Delivers ethinyl estradiol and progestin.
• New patch each week for 3 weeks, then
patch-free for one week.
107
Hormonal Contraceptives: Transdermal Patch Effectiveness & AE?
* The Patch is less effective in women >90 kg (198 lb) because of adipose tissue
* Break-through bleeding more common in first 2 cycles
* Skin irritation may be a problem
108
Vaginal Contraceptive Ring- (Not IUD) Administered?
* Inserted intravaginally by the patient
| * In place 3 weeks, one "ring-free" week
109
Vaginal Contraceptive Ring- (Not IUD) delivers & effectiveness?
* Delivers ethinyl estradiol and progestin
* Ring should not be removed for more than 3 hr
* Not effective until in place for 7 days
110
Vaginal Contraceptive Ring- (Not IUD) advantage & adverse effects?
• Rapid return to fertility after removal
• Discomfort, headaches and vaginal discharge are
adverse effects
111
Hormonal Contraceptives: Injectable Contraceptives
| Progesterone only is?
Usually medroxyprogesterone
112
Hormonal Contraceptives: Injectable Contraceptives: Given how often?
* Intramuscular and Subcutaneous preparations
| * Injected every 3 months
113
Hormonal Contraceptives: Injectable Contraceptives:
| Adverse effects & disadvantages?
* Amenorrhea common, irregular bleeding can occur
* Adverse effects – weight gain, headache, decreased bone density
* Discontinue after 2 years unless no alternative
* Delayed return to fertility (6-12 months)
114
Hormonal Contraceptives: Implant
| Progesterone only is?
Usually etonogestrel.
115
Hormonal Contraceptives: Implant administered & adverse effects?
* Single rod implanted under the skin (upper arm)
* Effective for 3 years
* Adverse effects – same as all progestins
116
INTRAUTERINE CONTRACEPTIVE DEVICES (IUDs) Two types of IUD :
* Copper containing (copper is spermacidal). Effective 15-20 years (FDA recommends 10 yr)
* Progestin releasing (20 mcg/day levonorgestrel) Release rate decreases with time (FDA – 5yr limit).
117
INTRAUTERINE CONTRACEPTIVE DEVICES (IUDs) Advantages & Disadvantages?
* Fertility quickly restored after removal
* Less blood loss – FDA approved for dysmenorrhea
* Adverse effects: copper may cause cramping; progestin-irregular bleeding (6-12 mo)
* High initial cost. Very low overall cost.
118
BARRIER CONTRACEPTIVE DEVICES Types & functions?
• Male and female condoms
– Protect against HIV and STDs
• Diaphragms and cervical caps
– With spermicide (in place 6 hr before and after)
– Protection against HIV and STDs unclear
119
BARRIER CONTRACEPTIVE DEVICES Adverse effects:
Less effective than hormone contraceptives or IUDs.
120
SPERMICIDES Most common is?
Nonoxynol-9, a surfactant. Available in foams, gels, creams & suppositories, also used as lubricant for condoms, diaphragms
121
Nonoxynol-9 dose effectiveness & adverse effects?
• 100 to 150 mg dose is best
• Effective for only 1 hr, reapplication necessary
• Must be in contact with the cervix
• Adverse effects: less effective, irritation of vaginal
mucosa, toxic shock syndrome
122
SPONGE: mechanism, effectiveness, & adverse effects?
* Barrier containing Nonoxynol-9
* Moisten in water, place over cervix
* Effective immediately and for up to 24 hr
* Must remain in place 6 hr after intercourse
* Adverse effects: inferior to diaphragms
123
FERTILITY AWARENESS METHODS examples & effectiveness?
• "Calendar method" based on calculated time of
ovulation
• Ovulation detected by increased body temperature
• Avoid intercourse on presumed fertile days
• Relatively high failure rates
124
EMERGENCY CONTRACEPTION mechanism?
Prevent or delay ovulation
125
EMERGENCY CONTRACEPTION Progestins (levonorgestrel) dose effectiveness?
• Progestins (levonorgestrel) 2 doses 12 hr apart
• Can prevent 50-80% of pregnancies
• Best if taken within 24 to 72 hr of intercourse
• Usually available without prescription for women
17 years or older
126
EMERGENCY CONTRACEPTION Ethics?
• Ethics questions for physicians & pharmacists?
• Contraception has always been controversial
ethically and/or legally! In 1960's birth control pills were only available to married women!
127
EMERGENCY CONTRACEPTION Other Alternatives & adverse effects?
• Many oral contraceptives can be used. Different
doses (1.5 mg levonorgestrel). Not recommended
• Vomiting within 1 hr suggests repeated dose
• Copper IUD inserted within 5 days
• None are as effective as two dose progestin
• Adverse effects: Nausea and vomiting with
ethinyl estradiol, headache, breast tenderness,
and abdominal pain.
128
```
Postcoital Contraception (Morning after pill) there are now two FDA approved preparations that
consist of two doses of?
```
Levonorgestrel separated by 12 hours (first dose within 72 hours of intercourse). Now over-the-counter with some state control regarding age, etc.
129
Antiprogestins or Contragestation drugs:
* Mifepristone
| * Onapristone
130
Mifepristone (the first antiprogestin, RU 486) is now
| approved by the FDA for the?
termination of pregnancy (49 days or less into
pregnancy). [State laws regulate dispensing!] Mifepristone blocks binding of progesterone to its
receptor.
131
Onapristone more pure
antagonist of progesterone.
132
Binding of testosterone to androgen receptor which binds to DNA response element causes?
Tissue specific transcription coactivators & corepressors allow different effects in different tissues.
133
Conversion of testosterone in some tissues (in prostate, but not in muscle or kidney) to?
5α-dihydrotestosterone (DHT) which binds to the androgen receptor.
134
DHT more potent than?
testosterone, binds 10x tighter.
135
testosterone conversion to estradiol by?
Aromatases
136
Primary Uses of Androgens Men & Women?
* Androgen-deficient men (replacement) for development or maintenance of male sex characteristics. IM injection most effective
* Treatment of Endometriosis & PMS (danazol) = advantageous because weakly androgenic
137
Use as anabolic agents (anabolic steroids)
- some androgens are less androgenic than testosterone but have significant anabolic effects
- abused by athletes
- side effects are serious: lower testosterone levels, decreased libido, decreased spermatogenesis, increased hepatotoxicity, development of CHD
- may be useful in children to promote linear growth
138
Absorption, Metabolism, Excretion Testosterone:
- Administered by injection or by mouth both result in rapid metabolism
- Other routes of administration are better (transdermal patches)
- Testosterone esters are more lipid soluble, have longer duration of action.
- Alkylation at the 17-α position allows testosterone administration by mouth because it decreases hepatic metabolism.
139
Administration Duration
| methyltestosterone
oral
| short
140
Administration Duration
| testosterone propionate
IM
| short
141
Administration Duration
| testosterone cypionate
IM
| long
142
Administration Duration
| testosterone enanthate
IM
| long
143
Administration Duration
| fluoxymesterone
oral
| short
144
Administration Duration
| danazol
IM
| long
145
Androgen supplements are currently used in?
Elderly men (primarily testosterone) to maintain muscle mass.
146
Although transdermal patches are available?
Most men prefer injections because of tearing of skin when patch is removed.
147
Androgen Supplements Side Effects:
* Dose related
* Virilizing effects when used in females (facial hair, voice changes)
* Feminizing effects when used in males due to testosterone conversion to estradiol
* Suppression of LH & FSH secretion leading to decreased size of testis, decreased spermatogenesis, decreased endogenous testosterone synthesis. NOT useful as male contraceptives because zero sperm count cannot be achieved.
* Decreased HDL & increased LDL levels increasing risk of CHD.
148
Androgen Receptor Antagonists Drugs?
Cyproterone acetate
Flutamide
Bicalutamide
Nicalutamide
149
Cyproterone acetate competes with?
DHT for the androgen receptor, prevents translocation into the nucleus.
150
Cyproterone acetate used in treatment of?
Acne, baldness, hirsutism, virilizing syndrome, inhibits libido in sex deviant males.
151
Flutamide, bicalutamide, & nicalutamide used in treatment of?
prostate cancer
152
Nicalutamide replacing flutamide because of?
Lower hepatic toxicity & once a day administration (vs. 3x)
153
Inhibitors of 5α-Reductase cause?
inhibition of DHT production
154
Inhibitors of 5α-Reductase drug?
Finasteride
155
Antagonists of 5α-reductase, blocks?
Testosterone conversion to DHT
156
Finasteride treatment for?
- treatment for benign prostatic hyperplasia
| - now approved for treatment of male pattern baldness
157
Finasteride adverse effects?
Should not be touched by pregnant women, absorbed through skin & can cause birth defect in male fetus. Men should not donate blood.
