Adverse effects of SERMs

Adverse effects of SERMs:
1- Tamoxifen:
• Hot flashes & nausea. Menstrual irregularities & vaginal bleeding can also occur.
• Due to its estrogenic activity in the endometrium, hyperplasia & malignancies. This has led to recommendations for limiting the length of time on the drug for some indications.
• Because it is metabolized by various CYP450 isozymes, tamoxifen is subject to many drug interactions. Some CYP450 inhibitors may prevent the formation of active metabolites of tamoxifen & possibly reduce the efficacy (for example, amiodarone, haloperidol, risperidone). Thus, concurrent drug therapy should be reviewed carefully to screen for potential drug interactions with tamoxifen.
2- Raloxifene
• Similar to tamoxifen, hot flashes & leg cramps are common adverse effects with raloxifene.
Note: Raloxifene apparently has little to no effect on the endometrium & therefore, may not predispose to uterine cancer.
• In addition, there is an increased risk of deep-vein thrombosis, pulmonary embolism & retinal-vein thrombosis. Women who have a past or active history of venous thromboembolic events should not take the drug.
• Should be avoided in women who are or may become pregnant.
• Coadministration with cholestyramine can reduce the absorption of raloxifene by 60 %. Therefore, these drugs should not be taken together.
3- Toremifene similar to those of tamoxifen. Data on the risk of the endometrium,
hyperplasia & cancer are lacking.
4- Clomiphene
• Its adverse effects are dose related, they include headache, nausea, vasomotor flushes, visual disturbances & ovarian enlargement.
• The risk of multiple births (twins or triplets) with clomiphene is 3 - 5 %.

Progestogens
Progesterone, the natural progestogen, is produced in response to LH by both females (secreted by the corpus luteum, primarily during the second half of the menstrual cycle & by the placenta) & by males (secreted by the testes). It is also synthesized by the adrenal cortex in both sexes.
• In females, progesterone promotes the development of a secretory endometrium
• The high levels of progesterone that are released during the second half of the menstrual cycle (the luteal phase) inhibit the production of gonadotropin &, therefore, prevent further ovulation. If conception takes place, progesterone continues to be secreted, maintaining the endometrium in a favorable state for the continuation of the pregnancy & reducing uterine contractions. If conception does not take place, the release of progesterone from the corpus luteum ceases abruptly. This decline stimulates the onset of menstruation.


Mechanism of action
Like other steroid hormones, they cause:
1) An increase in hepatic glycogen, probably through an insulin-mediated mechanism.
2) A decrease in Na+ reabsorption in the kidney due to competition with aldosterone
at the mineralocorticoid receptor.
3) An increase in body temperature through an unknown mechanism.
4) A decrease in some plasma amino acids.
5) An increase in excretion of urinary nitrogen.

Therapeutic uses of progestogens
• The major clinical uses of progestogens are to treat a hormonal deficiency & for contraception.
• For contraception, they are generally used with estrogens, either in combination or in a sequential manner.
• Progesterone by itself is not used widely as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability.
• Synthetic progestogens (progestins) used in contraception are more stable to first-pass metabolism, they include Norethindrone, Norethindrone acetate, Norgestrel, Levonorgestrel, Desogestrel, Norgestimate & Drospirenone.
• Most synthetic progestins used in oral contraceptives (eg.Norethindrone, Norethindrone acetate, Norgestrel, Levonorgestrel) are derived from 19-nortestosterone & possess some androgenic activity because of their structural similarity to testosterone.
• Medroxyprogesterone acetate is an injectable contraceptive & the oral form is a common progestin component of postmenopausal HT.
• Progestins are also used for the control of dysfunctional uterine bleeding, treatment of dysmenorrhea & management of endometriosis & infertility.

Pharmacokinetics
• A micronized preparation of progesterone is rapidly absorbed after oral administration & has a short half-life in the plasma & is almost completely metabolized by the liver. The glucuronidated metabolite is excreted primarily by the kidney.
• Synthetic progestins are less rapidly metabolized.
• Oral medroxyprogesterone acetate has a half-life of 30 days, when injected IM or SC it has a half-life of about 40 - 50 days & provides contraceptive activity for approximately 3 months.
• The other progestins have half-lives of 1 - 3 days, allowing for once-daily dosing.

Adverse effects
• Headache, depression, weight gain & changes in libido.
• The 19-nortestosterone derivatives, have androgenic activity & can increase the ratio of LDL to HDL cholesterol & cause acne & hirsutism. Less androgenic progestins, such as norgestimate & drospirenone, may be preferred in women with acne.
• Injectable medroxyprogesterone acetate has been associated with an increased risk of osteoporosis, which has led to recommendations for limiting the duration of use to 2 years unless other forms of contraception are unsatisfactory.

Antiprogestin
Mifepristone
• A progesterone antagonist with partial agonist activity (note: Mifepristone also has potent antiglucocorticoid activity), its administration to females early in pregnancy usually results in abortion of the fetus due to interference with the progesterone needed to maintain pregnancy.
• Mifepristone is often combined with the PGE1 analog misoprostol (orally or intravaginally) to induce uterine contractions. This combination increases the chance for successful termination of pregnancy.
• The major adverse effects are significant uterine bleeding & the possibility of an incomplete abortion.
• Mifepristone has also been investigated as an oral contraceptive & an emergency contraceptive agent.

Contraceptives
They decrease fertility by different mechanisms, such as:
1. Preventing ovulation.
2. Impairing gametogenesis or gamete maturation.
3. Interfering with gestation.
Currently, interference with ovulation is the most common pharmacologic intervention for preventing pregnancy.

Major classes of contraceptives
1. Combination oral contraceptives (COCPs):
• Products containing a combination of an estrogen & a progestin are the most common type of oral contraceptives.
• Monophasic combination pills contain a constant dose of estrogen & progestin given over 21 days.
• Triphasic oral contraceptive products attempt to mimic the natural female cycle & most contain a constant dose of estrogen with increasing doses of progestin given over three successive 7-day periods.
• With either type of combination oral contraceptive, active pills are taken for 21 days followed by 7 days of placebo. Withdrawal bleeding occurs during the hormone-free interval.
Note: Most common estrogen in the combination pills is ethinyl estradiol & the most common progestins are norethindrone, norethindrone acetate, norgestrel, levonorgestrel, desogestrel, norgestimate & drospirenone.
• COCPs are highly effective in achieving contraception.
• Use of extended-cycle contraception (84 active pills followed by 7 days of placebo) results in less frequent withdrawal bleeding.
• A continuous oral contraceptive product (active pills taken 365 days of the year) is also available.

2. Transdermal contraceptive patch:
• An alternative to COCPs.
• it containing ethinyl estradiol & the progestin norelgestromin.
• One contraceptive patch is applied each week for 3 weeks to the abdomen, upper torso, or buttock. Week 4 is patch free & withdrawal bleeding occurs.
• Its efficacy is comparable to that of the oral contraceptives, but it has been shown to be less effective in women weighing greater than 90 kg.
• Contraindications & adverse effects for the patch are similar to those of oral contraceptives.
• Pharmacokinetic studies have indicated that total estrogen exposure with the transdermal patch is up to 60 % greater than that seen with a 35-?g estrogen oral contraceptive.
• Increased exposure to estrogen may increase the risk of adverse events such as
thromboembolism.

3. Vaginal ring:
• An additional contraceptive option is a vaginal ring containing ethinyl estradiol & etonogestrel.
• The ring is inserted into the vagina & is left for 3 weeks, week 4 is ring free & withdrawal bleeding occurs.
• Its efficacy, contraindications & adverse effects are similar to those of COCPs.
• One caveat with the vaginal ring is that it may occasionally slip or be expelled accidentally.

4. Progestin-only pills (mini-pill):
• They usually containing, norethindrone, are taken daily on a continuous schedule.
• Progestin-only pills deliver a low, continuous dosage of drug.
• They are less effective than the combination pill & they may produce irregular menstrual cycles more frequently than the combination product.
• Has limited patient acceptance because of anxiety over the increased possibility of pregnancy & the frequent occurrence of menstrual irregularities.
• The progestin-only pill may be used for patients who are breastfeeding (unlike estrogen, progestins do not have an effect on milk production), are intolerant to estrogen, are smokers, or have other contraindications to estrogen-containing products.

5. Injectable progestin:
• Medroxyprogesterone acetate is an injectable contraceptive that is administered every 3 months. It is available in both IM & SC injection formulations.
• Weight gain is a common adverse effect of medroxyprogesterone acetate.
• Because this product provides high sustained levels of progestin, many women experience amenorrhea with medroxyprogesterone acetate. In addition, return to fertility may be delayed for several months after discontinuing use of this agent.
• Medroxyprogesterone acetate may contribute to bone loss & predispose patients to osteoporosis and/or fractures Therefore, the drug should not be continued for more than 2 years unless the patient is unable to tolerate other contraceptive options.

6. Progestin implants:
• A subdermal implant containing etonogestrel offers long-term contraception. One 4-cm capsule is placed subdermally in the upper arm & provides contraception for approximately 3 years.
• The implant is nearly as reliable as sterilization & the effect is totally reversible when surgically removed.
• Once the progestin-containing capsule is implanted, this method of contraception does not rely on patient compliance. This may, in part, explain the low failure rate for this method.
• Principal side effects of the implants are irregular menstrual bleeding & headaches. The etonogestrel implant has not been studied in women who weigh more than 130% of ideal body weight & may be less effective in this population.

7. Progestin intrauterine device:
• A levonorgestrel-releasing intrauterine system offers a highly effective method of long-term contraception.
• Provides contraception for up to 5 years.
• Suitable for women who already have at least one child & do not have a history of pelvic inflammatory disease or ectopic pregnancy.

8. Postcoital contraception:
• The overall risk of pregnancy after an episode of coitus without effective contraception is shown in Figure 25.10.
• Postcoital or emergency contraception reduces the probability of pregnancy to between 0.2 and 3 %.
• Emergency contraception uses high doses of progestin (eg. 0.75 mg of levonorgestrel) or high doses of estrogen (100 ?g of ethinyl estradiol) plus progestin (0.5 mg of levonorgestrel) administered within 72 hours of unprotected intercourse (the “morning-after pill”). For these regimens, a second dose of emergency contraception should be taken 12 hours after the first dose.
• A newer progestin-only regimen consists of a one-time dose of 1.5 mg levonorgestrel.
• For maximum effectiveness, emergency contraception should be taken as soon as possible after unprotected intercourse & preferably within 72 hours.
• The progestin-only emergency contraceptive regimens are generally better tolerated than the estrogen-progestin combination regimens.
• A single dose of mifepristone has also been used for emergency contraception.
Mechanism of action
The mechanism of action for these hormonal contraceptives is not completely understood.
• It is likely that the combination of estrogen & progestin administered over an approximately 3-week period inhibits ovulation.
Note: The estrogen provides a negative feedback on the release of LH & FSH, thus preventing ovulation. The progestin also inhibits LH release & thickens the cervical mucus, thus hampering the transport of sperm. Withdrawal of the progestin stimulates menstrual bleeding during the placebo week.

Adverse effects
Most are believed to be due to the estrogen component, but CV effects reflect the action of both estrogen & progestin. The incidence of adverse effects with OCPs is relatively low & is determined by the specific compounds & combinations used.

1. Major adverse effects: breast fullness, depression, fluid retention, headache, nausea, and vomiting.

2. Cardiovascular: Although rare, the most serious one is CV disease, including thromboembolism, thrombophlebitis, HT, increased incidence of MI & cerebral & coronary thrombosis. These adverse effects are most common among smoker women & who are older than age 35 years, although they may affect women of any age.

3. Carcinogenicity: OCPs have been shown to decrease the incidence of endometrial & ovarian cancer. The incidence of cervical cancer may be increased, because women are less likely to use additional barrier methods of contraception that reduce exposure to human papilloma virus (the primary risk factor for cervical cancer). The ability of OCPs to induce other neoplasms is controversial. The production of benign tumors of the liver that may rupture & hemorrhage is rare.

4. Metabolic: Abnormal glucose tolerance (similar to the changes seen in pregnancy) is sometimes associated with oral contraceptives.
Weight gain is common in women who are taking the nortestosterone derivatives. Weight gain may be less with oral contraceptives containing drospirenone.

5. Serum lipids: The combination pill causes a change in the serum lipoprotein profile: Estrogen causes an increase in HDL & a decrease in LDL (a desirable occurrence), whereas progestins may negate some of the beneficial effects of estrogen. Therefore, estrogen- dominant preparations are best for individuals with elevated serum cholesterol.

6. Contraindications: Oral contraceptives are contraindicated in the presence of cerebrovascular & thromboembolic disease, estrogen dependent neoplasms, liver disease & pregnancy. Combination oral contraceptives should not be used in patients over the age of 35 who are heavy smokers.


Androgens
• A group of steroids that have anabolic and/or masculinizing effects in both males & females.
• Testosterone, the most important androgen in humans, is synthesized by Leydig cells in the testes & in smaller amounts, by thecal cells in the ovary of the female & by the adrenal gland in both sexes.
• Other androgens secreted by the testes are 5?-dihydrotestosterone (DHT), androstenedione & dehydroepiandrosterone (DHEA) in small amounts. In adult males, testosterone secretion by Leydig cells is controlled by gonadotropin-releasing hormone (Gn-RH) from the hypothalamus, stimulating the anterior pituitary gland to secrete FSH & LH (which was originally known as interstitial cell-stimulating hormone, (ICSH) in males).
[Note: LH stimulates steroidogenesis in the Leydig cells, whereas FSH is necessary for the initiation of spermatogenesis.]
Testosterone or its active metabolite (DHT) inhibits production of these specific trophic hormones through a negative feedback loop and thus, regulates testosterone production.
The androgens are required for:
1. Normal maturation in the male
2. Sperm production.
3. Increased synthesis of muscle proteins & Hb.
4. Decreased bone resorption.
Synthetic modifications of the androgen structure are designed to (1) modify solubility and susceptibility to enzymatic breakdown (thus prolonging the half-life of the hormone), and (2) separate anabolic and androgenic effects.

Mechanism of action:
Like the estrogens and progestins, androgens bind to a specific nuclear receptor in a target cell. Although testosterone itself is the active ligand in muscle and liver, in other tissues it must be metabolized to derivatives such as DHT. For example, after diffusing into the cells of the prostate, seminal vesicles, epididymis and skin, testosterone is converted by 5-a-reductase to DHT, which binds to the receptor.
In the brain, liver & adipose tissue, testosterone is biotransformed to estradiol by cytochrome P450 aromatase. The hormone/receptor complex binds to DNA and stimulates the synthesis of specific RNAs and proteins.
[Note: Testosterone analogs that cannot be converted to DHT have less effect on the reproductive system than they do on the skeletal musculature.]

Therapeutic uses
1. Androgenic effects: Androgenic steroids are used in males with inadequate androgen secretion. [Note: Hypogonadism can be due to Leydig cell dysfunction or, secondarily, to failure of the hypothalamus or pituitary. In each instance, androgen is indicated.]

2. Anabolic effects: Anabolic steroids can be used to treat senile osteoporosis & chronic wasting associated with human immunodeficiency virus or cancer. They may also be used as adjunct therapy in severe burns & to speed recovery from surgery or chronic debilitating disease.

3. Endometriosis: Danazol, a mild androgen, is used in the treatment of endometriosis (ectopic growth of the endometrium) & fibrocystic breast disease.
It inhibits release of FSH & LH but has no effect on the aromatase. Weight gain, acne, decreased breast size, deepening voice, increased libido & increased hair growth are among the adverse effects.
Danazol has been reported occasionally to suppress adrenal function.

5. Unapproved use: Anabolic steroids are used to increase lean body mass, muscle strength and endurance in athletes & body builder. In some popular publications, DHEA (a precursor of testosterone & estrogen) has been touted as the anti-aging hormone as well as a "performance enhancer". With its ready availability in health food stores, the drug has been abused. There is no definitive evidence that it slows aging, however, or that it improves performance at normal therapeutic doses.

Pharmacokinetics
1. Testosterone:
• Ineffective orally (inactivated by first-pass metabolism).
• As with the other sex steroids, testosterone is rapidly absorbed & is metabolized to relatively or completely inactive compounds that are excreted primarily in the urine.
• Testosterone & its C17-esters of testosterone (eg. testosterone cypionate or enanthate) are administered intramuscularly.
Note: The addition of the esterified lipid makes the hormone more lipid soluble, thereby increasing its duration of action.
• Transdermal patches, topical gels & buccal tablets of testosterone are also available.
• Testosterone & its esters demonstrate a 1:1 relative ratio of androgenic to anabolic activity.
2. Testosterone derivatives:
• Alkylation of the 17? position of testosterone allows oral administration of the hormone.
• Agents such as fluoxymesterone have a longer half-life in the body than that of the naturally occurring androgen.
• Fluoxymesterone is effective when given orally & it has a 1:2 androgenic to anabolic ratio.
• Oxandrolone is another orally active testosterone derivative with anabolic activity 3 to 13 times that of testosterone.
• Hepatic adverse effects have been associated with the 17 ? -alkylated androgens.

Adverse effects
1. In females:
• Masculinization, acne, growth of facial hair, deepening of the voice, male pattern baldness & excessive muscle development. Menstrual irregularities may also occur.
• Testosterone should not be used by pregnant women because of possible virilization of the female fetus.
2. In males:
• Excess androgens can cause priapism, impotence, decreased spermatogenesis & gynecomastia.
• Cosmetic changes such as those described for females may occur as well.
• Androgens can also stimulate growth of the prostate.
3. In children:
• Androgens can cause abnormal sexual maturation & growth disturbances resulting from premature closing of the epiphyseal plates.
4. General effects:
• Androgens increase serum LDL & lower serum HDL levels thus, increasing LDL:HDL ratio & potentially increase the risk for premature coronary heart disease.
• Can also cause fluid retention, leading to edema.
5. In athletes:
• Use of anabolic steroids, (eg, DHEA) by athletes can cause premature closing of the epiphysis of the long bones, which stunts growth & interrupts development.
• High doses taken by young athletes may result in reduction of testicular size, hepatic abnormalities, increased aggression (“roid rage”), major mood disorders & other adverse effects described above.

Antiandrogens
• They counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors.
• For example, at high doses, the antifungal drug ketoconazole inhibits several of the CYP450 enzymes involved in steroid synthesis.
• Finasteride and dutasteride, agents used for the treatment of benign prostatic hypertrophy, inhibit 5?-reductase. The resulting decrease in formation of DHT in the prostate leads to a reduction in prostate size.
• Antiandrogens, such as flutamide, act as competitive inhibitors of androgens at the target cell. Flutamide is used in the treatment of prostatic carcinoma in males. Two other potent antiandrogens, bicalutamide and nilutamide, are effective orally for the treatment of prostate cancer.