Module 20 Flashcards
What is the major structural feature that separates androgens and estrogens? How is this difference used to treat cancer?
- Testosterone is the precursor to estradiol. As far as I know all estrogens have a phenol functional group. (You should be able to recognize the phenolic group on estradiol; it is the OH group on the aromatic ring on the lower left side of the estradiol molecule.)
- There are some prodrugs such as tamoxifen that are not phenols but require metabolism to have estrogenic activity. The enzyme that mediates the conversion of testosterone to estradiol is aromatase. One of the treatments for estrogen-dependent breast cancer is aromatase inhibitors.
What are Selective Estrogen Receptor Modulators (SERMs)? What theories have been proposed to explain the agonist/antagonist action of these agents? What are their approved indications, and what are their potential uses? Should all women who are at increased risk of breast cancer receive raloxifene?
- Instead of having estrogenic effects in all tissues, SERMs can have estrogenic effects in some tissues and anti-estrogenic effects in other tissues. One of the earliest SERMs was tamoxifen, which has estrogenic effects in bone and the uterus but anti-estrogenic effects in breast. Therefore, it is used to treat estrogen-dependent breast cancer; however, it has the potential to increase the risk of uterine cancer.
- In contrast raloxifene has estrogenic effects in bone, but it has anti-estrogenic effects in both breast and uterus and is used primarily to treat osteoporosis.
- SERMs have been used to treat a variety of symptoms of menopause, even poor memory, but the use of estrogen and SERMs has decreased. The basis for the differences in agonist and antagonist effects of different SERMs is complex. Part of it is due to different estrogen receptor subtypes with different tissue distributions, but it is more complex than that and involves other factors such as co-receptors.
What is the more recent data on the risks and benefits of postmenopausal estrogen? How does this compare with the older data, and if the recent data is correct, how could we have gotten it so wrong?
- Most of the early studies suggested that the use of estrogen to treat the symptoms of menopause was associated with a wide variety of benefits; it was virtually the fountain of youth. However these were mostly case control studies; none were prospective randomized studies.
- Finally a prospective randomized study was performed, not an easy thing to do, and virtually all of the effects were negative, especially on cardiovascular disease and breast cancer. This study was criticized because it involved mostly older women, and they took estrogen for an extended period of time.
- It appears that if estrogen is given for a short period of time in the perimenopausal period it has no significant effect on heart disease, but it still leads to a small increase in the risk of stroke. Estrogen also appears to increase the risk of breast cancer up to 3 fold, especially when initiated early in the perimenopausal period, but it is conceivable that estrogen promotes and makes it easier to detect less malignant forms of breast cancer easier without significantly increasing mortality.
What are tissue selective estrogen complexes (TSEC)?
A TSEC is a combination of an estrogen and a SERM, e.g. conjugated estrogens combined with bazedoxifene. Bazedoxifene antagonizes the effects of estrogen on the breast and uterus.
What is the source of Premarin, and what does it contain that is not present in human estrogens?
- Premarin is short for pregnant mare’s urine. There are stables of horses that are kept pregnant, and their urine is collected, and the conjugated estrogens purified.
Although it is claimed that Premarin is “natural”, estrogens such as equilin are only natural to a horse
What are phytoestrogens? Are they effective in treating the symptoms of menopause? What is the evidence for benefit or harm with respect to the risk of breast and endometrial cancer?
- Phytoestrogens are plant-derived chemicals that have estrogenic activity. Most of the studies involving these agents are of poor quality and a Cochrane review concluded that there was no conclusive evidence that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes or night sweats in perimenopausal women.
Phytoestrogens do not appear to increase or decrease the risk of breast or endometrial cancer, but the studies are insufficient to be confident because the studies were either of short duration (median 6.2 months) or not randomized
Describe the evidence for efficacy and toxicity of black cohosh for treating the symptoms of menopause.
some studies suggest that black cohosh is effective in decreasing symptoms of menopause. However, the better studies show no significant benefit. There are reports of liver failure associated with the use of black cohosh. There is a meta analysis that suggests that black cohosh does not increase the risk of liver injury. However, the numbers of patients are much too small to detect serious injury, and the design of the individual studies would have likely missed mild injury, which is more common than serious injury, because they only measured ALT at the end of the study, and mild injury usually resolves despite continued treatment
What is the rationale for using estrogen patches rather than oral administration?
- A major side effect of estrogen is the increased risk of thromboembolism. This is because estrogen increases the synthesis of clotting factors in the liver.
- There is significant first pass metabolism of estrogen in the liver, and exposure of the liver to estrogen is much higher when it is administered orally than if administered by a transdermal patch.
What are the side-effects of anabolic steroids?
Effects of anabolic steroids include increased low-density lipoprotein with an increased risk of cardiovascular disease, high blood pressure, liver injury, gynecomastia, testicular atrophy and sterility. They can probably increase aggression (roid rage), although that is more controversial.
The UofT pharmacology textbook states that 5-alpha-reductase inhibitors are under investigation. In fact one agent has been available for many years. What is it, what is the indication for its use, what is its mechanism of action, and what is the evidence for its efficacy? What other indication has been approved for this agent? What precaution may the spouse need to be informed of?
- Finasteride was the first potent 5-alpha-reductase inhibitor developed to treat benign prostatic hyperplasia, and a newer agent is dutasteride. It inhibits the conversion of testosterone to dihydrotestosterone, which has more effects on the prostate than testosterone.
- It has not been as effective as expected for the treatment of benign prostatic hypertrophy; even when it shrinks the prostate, the effect on obstruction is less.
It is present in semen of a treated man, and it is so potent that it can affect a male fetus if a man taking the drug has sex with a pregnant woman. Pregnant pharmacists also need to be careful when handling finasteride or dutasteride. It has also been used to treat male pattern baldness because dihydrotestosterone is also the major hormone affecting hair growth.
- It has not been as effective as expected for the treatment of benign prostatic hypertrophy; even when it shrinks the prostate, the effect on obstruction is less.
