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MS II Pharmacology Unit 1 > Reproductive Pharmacology > Flashcards

Reproductive Pharmacology Flashcards

1
Q

What is the follicular phase?

A
  • early- days 1-7. Menstruation occurs at the beginning of the follicular phase. FSH and LH levels are increased relative to baseline. Estrogen and progesterone levels are low
  • late: days 7-14. Growth, maturation of ovarian follicles and one follicle becomes dominant in growth and hormone secretion. FSH levels decrease (due to negative feedback) and estrogen levels increase (due to positive feedback). Progesterone levels remain low. Endometrial lining continues to grow and thicken
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2
Q

What is the ovulatory phase?

A

-pre-ovulation and ovulation: Fays 13-14. LH surge stimulates follicular rupture and ovulation occurs within 48 hours

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3
Q

What is the luteal phase?

A
  • the ruptured follicile develops into the corpus luteum which produces large amounts of progesterone and estrogen
  • progesterone facilitates a thickening of the endometrial lining and the development of blood vessels
  • in the absence of fertilization, the corpus luteum begins to degenerate and ceases hormone production
  • as a result the levels of estrogen and progesterone drop and menstruation occurs
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4
Q

What is the control of Gonadotropin secretion?

A

-Hypothalamus GnRH causes Anterior Pituitary LH and FSH, and then the ovaries produce estrogens and progesterone

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5
Q

What are the types of estrogens?

A
  • Natural estrogens- Estradiol (estradoil-17B, E2); Estrone (E1); Estriol (E3)
  • Synthetic estrogens- Steroidal synthetic estrogens- eythinyl estradiol; Mestranol; Quinestrol
  • Nonsteroidal synthetic estrogens- Diethylstilbestrol, Chlorotrianisene; Methallenestril
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6
Q

WHat is the structure of estrogen?

A
  • all steroidal estrogen derivatives are 18-carbon steroids, containing 4 rings (A,B,C,D)
  • estrogen derivatives contain different substitutions at carbon 3 and 17
  • A ring structure is essential for high-affinity binding of estrogen to its receptor
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7
Q

What is natural estrogen?

A
  • three major estrogens produced by the female body are estradiol (estradiol-17B, E2), estrone (E1), and Estriol (E3)
  • the ovary is the primary source of estradiol in premenopausal women
  • granulosa cells of ovarian follicles are generally responsible for making estrogens
  • estradiol can be converted to estrone and estriol in the liver
  • estrogens are convered from androstenedione and testosterone in ovaries or in other tissues (adipose tissues, bone and brain)- especially in men and post menopausal women, also placenta in pregnancy
  • estradoil plasma levels vary during menstrual cycle: early follicular phase: 50; preovulatory peak 350-850 pg/ml
  • the major circulating estrogen in premenopausal women is estradiol; for men and postmenopausal women it is estrone
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8
Q

What is the biosynthesis of estrogens

A
  • aromatase is involved in the production of estrogen
  • it converts testosterone to estradiol and androstendione to estrone
  • this enzyme is expressed by estrogen producing cells of the ovaries, placenta, adrenal gland, adipose tissues, testicles, and brain. It is important for estrogen biosynthesis
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9
Q

What are synthetic estrogens?

A

-include steroidal and nonsteroidal forms

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10
Q

What are the synthetic steroidal estrogens?

A
  • estradiol esters- estradiol valerate, estradiol cypionate
  • conjugated estrogens- estrone sulfate, equilin sulfate
  • alkyl estrogens- ethinyl estradiol, mestranol
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11
Q

What are nonsteroidal synthetic estrogens?

A
  • are less commonly used in clinics

- diethylstilbestrol (DES) was reported to increase the risk of clear cell adenocarcinoma in the vagina and cervix

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12
Q

What are the pharmacokinetics of estrogens?

A
  • estrogens used in therapy are absorbed through skin, mucous membranes, and the gastrointestinal tract
  • estrogens are widely distributed in the body. In circulation, estradiol binds strongly to sex hormone-binding globulin (SHBG)
  • it also binds to albumin with lower affinity
  • E2 is mainly metabolized in the liver to estrone (E1). Significant amounts of estrogens and their active metabolites are excreted in the bile and reabsorbed from the intestine
  • estadoil is not used orally frequently due to the extensive first pass effect. Micronization increases the half-life of estradiol and reduces its destruction in the GI tract
  • excretion of the inactive metabolites occurs via urine
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13
Q

How does estrogen affect female maturation?

A

-development of secondary sexual characteristics

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14
Q

Hows does estrogen effect the reproductive system?

A
  • stimulates proliferation of endometrium and follicular growth
  • stimulates breast cell growth
  • induces the synthesis of progesterone receptors
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15
Q

How does estrogen effect feedback of gonadotropin release?

A
  • when estrogen reaches high level, its acts in a negative feedback loop on anterior pituitary as well as hypothalamus and thus slows down the release of FSH and estrogen itself
  • positive feedback occurs at high concentrations near the end of the follicular phase, estrogen positively regulates pituitary to trigger the release of FSH and LH that causes the ovary to produce more estrogen
  • high levels of estrogen and LH are responsible for ovulation
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16
Q

What are the cardiovascular effect from estrogen?

A
  • whether estrogens reduce cardiovascular disease is still under debate
  • recent studies have shown that estrogen-alone hormone therapy had no effect on coronary heart disease risk but increases the risk of stroke and deep vein thrombosis for postmenopausal women
  • effects on lipoprotein: increase high-density lipoprotein (HDL) and decrease low-density lipoprotein (LDL) levels
  • both benefical and non-beneficial
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17
Q

How does estrogen effect bone and fat?

A
  • decrease bone resoprtion. Used for the treatment of osteoporosis
  • increase body fat, salt, and fluid retention- side effect
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18
Q

How is estrogen used?

A
  • Contraception
  • Primary hypogonadism
  • postmenopausal hormone therapy
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19
Q

How is estrogen used for contraception?

A

-synthetic estrogen, such as ethinyl estodiol, is frequently used along with Progestin for prevention of pregnancy

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20
Q

How is estrogen used to treat primary hypogonadism?

A
  • it is the reduced or absent secretion of hormones from the sex glands e.g. ovaries
  • used in replacement therapy in patients with estrogen-deficiency
21
Q

How is estrogen used in postmenopausal hormone therapy?

A
  • it is used to reduce postmenopause symptoms such as hot flashes, atrophic vaginits
  • also for the prevention of osteoporosis
22
Q

What are the common adverse effects of estrogen?

A
  • nausea
  • breast tension/pain
  • vaginal bleeding
  • headache
  • weigt gain
  • hypertension
23
Q

What are some less common effects of estrogens?

A
  • breast cancer- controversial. Previous studies showed increased risk in breast cancer with long term (>5 years) use. Recent studies showed no increased risk of breast cancer with estrogen alone
  • a 2-3 fold increase in the incidence of DVT and pulmonary embolism
  • increased risk of heart attack, stroke and gallbladder disease
  • may increase the risk of cervical and endometrial cancers
24
Q

What are the contraindications for estrogen treatment?

A
  • strongly contraindicated in patients with breast or endometrial cancer, endometriosis and undiagnosed vaginal bleeding
  • generally contraindicated in patients with pregnancy, thromboembolic disease, hypertension, hepatic disease or with family history of breast or uterine ancer
25
Q

What are anti-estrogen therapeautics?

A

-compounds that are estrogen receptor competitive antagonists (or partial agonists in some setting)

26
Q

What is Tamoxifen?

A
  • a nonsteroidal agent
  • has both estrogenic and antiestrogenic actions depending on the target tissues
  • antiestrogenic effect on mammary epithelium
  • pro-estrogenic effect on uterine endometrium and bone
27
Q

How does Tamoxifen effect mammary epithelium?

A
  • it works as a partial estrogen competitive antagonist in the breast
  • it blocks estrogen from binding to estrogen receptors (ER) and is commonly used for the treatment of ER- positive advanced breast cancer
28
Q

How is Tamoxifen used to treat breast cancer?

A
  • estrogen has much higher binding affinity for its receptor than that of Tamoxifen (about 100-1000x higher)
  • must be used in a concentration much higher than estrogen to maintain inhibition of breast cancer cells
  • available orally. Half life 7-14 hours, use 10-20 mg twice daily
29
Q

What is Tamoxifen’s effect on uterine epithelium?

A
  • it is a partial estrogen agonist in other tissues such as uterine endometrium and bone
  • the mechanisms for such effect are currently not clear
  • prolonged use of Tamoxifen (for prevention of breast cancer) increases incidence of endometrial carcinoma
30
Q

What is Clomiphene citrate?

A
  • a nonsteroidal agent, it has two isomrs, cis-chlomiphene (zuclomophene) and trans-chlomiphene (enclomiphene)
  • cis-clomphere 30% is a weak estrogen agnoist, trans- clomphene 70% is a potent antagonist
  • mechanism of action- blocks estrogen binding to its receptors in the hypothalamus and inhibits estradoils negative feedback on the gonadotropins -> increasees in the secretion of gonadotropins and LH and leads to ovulation
  • commonly used for stimulating ovulation in patients with disorders of ovulation who wish to become pregmany
  • oral 50-100mg daily for 5 days. Long half life 5-7 days
31
Q

What are the adverse effects of Clomiphene citrate?

A
  • symptoms of menopause (hot flashes)
  • stomach pain
  • headache
  • upset stomach
  • vomiting
  • multiple pregnancy
32
Q

What is progesterone?

A
  • secreted in females by the corpus luteum in the ovary. During pregnancy, high levels of progesterone are produced and secreted by the placenta
  • in males synthesized in the testis
  • also produced by the adrenal cortex in both sexes
  • production is stimulated by LH and gonadotropin
  • progesterone and progestin: two terms are commonly used interchangeably. More often, progestin is considered as synthetic progesterone
33
Q

What are the physiological functions of progesterone?

A
  • stimulates the endometrium to develop secretory glands and support fertilized egg implantation. Low levels of progesterone in the first several weeks of pregnancy may lead to a miscarriage
  • studies show progesterone has a growth suppressing effect on endometrial cancers. Long-term use of progesterone has atrophic effect on endometrium
  • high levels of progesterone trigger a negative feedback on the hypothalamus to stop releasing gonadotropin thus suppressing ovulation
34
Q

What are the general uses of progestins?

A
  • contraception- used in combo with estrogens or progetin-only
  • hormone replacement therapy- postmenopausal women. Progesterone counters the endometrial stimulatory effects of estrogen and reduces the risk of endometrial cancer
35
Q

What is Micronized progesterone?

A
  • PROMETRIM
  • natural progesterone has a short half-life (few minutes)
  • micronized progesterone increases the half life of progesterone, decreases first pass metabolism and enhances the dissolution of progesterone. Orally active
36
Q

What is transvaginal progesterone?

A
  • CRINONE
  • delivered throgh non-oral route (vaginal gel)
  • intravaginal administration produces uterine effects with minimal systemic side effects (avoid first pass metabolism and IM injections)
37
Q

What are synthetic progestins?

A
  • medroxyprogesterone, norethindrone, norgestrel, megestrol
  • -can be taken orally
  • considered to have strong androgenic activity and can cause hirsutism (excessive growth of hair) and acne
38
Q

What are the adverse effects of progestins?

A
  • natural- minimal- fatigue and drowsiness
  • synthetic progestins- have more side effects- edema, abdominal bloating, anxiety, irritability, depression, muscular pain
  • less common- increases risk of thombosis and pulmonary embolism
39
Q

What are the contraindications for progestins?

A
  • thromboembolic disorders or patients with a past history of such conditions
  • studies have shown that higher doses of progestin used for the treatment of abnormal vaginal bleeding increase the risk of thrombosis by 5-6x
  • liver disease or dysfunction- it is metabolized in the liver
  • undiagnosed vaginal bleeding
  • pregnancy- may have atropic effect on endometrium and may cause birth defects
40
Q

What are types of oral contraceptives?

A
  • estrogen-progestin combination
  • progestin-only
  • postcoital
  • reversible contraceptives
  • 3-8% failure rates due to poor patient compliance
41
Q

How does estrogen-progestin combination birth control work?

A
  • estrogenic agent- constant levels of estrogen suppress follicle stimulating hormone secretion thus prevents follicle maturation. Constant levels of estrogen can also suppress LH surge. The estrogenic component significantly contributes to COCs efficacy
  • progestational agent: progestin primarily suppresses LH secretion and thus prevent ovulation; thickens cervical mucus and makes it impenetrable to sperm; develops endometrial atrophy-making endometrium unreceptive to implantation
42
Q

How does progestin only oral contaceptive work?

A
  • commonly used: the mini pills
  • less effective than combo
  • useful when estrogens are contraindicated- studies show that progesterone has a growth suppressing effect on endometrial cancers, also good for lactating women
  • more likely to produce irregular menstrual cycle- why most women stop using
43
Q

Post-coital contaceptive

A
  • the morning after pill/ PLAN b
  • needs to be taken with 72 hours
  • mechanism not very clear, most likely works by interfering with implantation and inhibiting or delaying ovulation
  • can either have single tablet (1.5 mg) of levonorgestrel each day for up to 5 days after unprotected sex
44
Q

How does RU-486 work?

A
  • the abortion pill
  • consider as an antiprogestin
  • a synthetic steriod related to progesterone
  • the progestin antagonist. Competitively binds to progesterone receptor and blocks progesterone binding to its receptor
  • progesterone stimulates development of the uterine lining. RU-486 by blocking progesterones effect on uterus causes breakdown of uterine lining thus leading to detachment of embryo or feus
  • taken early in pregnancy it causes the embryo to be aborted- medical termination 49 days or less
  • 400-600 mg/d for 4 days or 800 for 2 daus
  • administered only by physician, if termination not completed surgical procedure is recommended
45
Q

Common causes ofED

A
  • diseases that lead to damage of nerves, arteries, smooth muscles and fibrous tissues are main causes of ED. These diseases include diabetes, vascular disease, kidney disease, MS, atherosclerosis and neurologic disease
  • injury of spinal cord or nerves, arteries near penis
  • psychological factors: stress, anxiety, guilt, depression
  • unhealthy lifestyle- smoking, alcoholism
46
Q

What are the treatment options for ED?

A
  • Sildenafil citrate- Viagra
  • Vardenafil HCL- Levitra
  • IC351, tadalafil (Cialis)
  • they are all phosphodiesterase type 5 inhibitors (PDE5i)
  • PDE5 is an enzyme which expresses predominately in the corpus cavernosum and the retina
  • however this enzyme also expresses in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle and skeletal muscle
47
Q

What is the mechanism of action for the PDE5 inhibitor?

A

sexual arousal -> NO released from synapse of neurons in corpus cavernosum -> accumulation of GTP -> cGMP (because PDE5 is inhibited this stays around longer) -> decreased Ca2+ -> smooth muscle relexation -> penile erection
-PDE5 inhibitors do not trigger an automatic erection but improve the response to sexual stimulation

48
Q

What is the half life and pharmacokinetics of PDE5 inhibitors?

A
  • half life: Viagra and Levitra- 4 h, Cialis- 17.5 h
  • pharmacokinetics: all three PDE5 inhibitors can be absorbed rapidly from the GI tract, peak plasma concentrations can be reaches in 1-2 hours
  • first line treatment
49
Q

What are the side effects of PDE5 inhibitors?

A
  • headache
  • dizziness
  • flushing and change in vision
  • upset stomach
  • stuffy or runny nose
  • UTI
  • diarrhea
  • some men have loss of vision maybe because of non-artertic anterior ischemic optic neuropathy, which may be caused by sudden decreased blood flow to the optic nerve
  • can cause sudden blood pressure drop to unsafe level when taken with other drugs such as nitrates and alpha blockers
  • should not be used more than once a day

MS II Pharmacology Unit 1 (10 decks)

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