Systemic Pharmacology: Lecture 25 Drugs Acting on Endocrine System Part 3

What is the mechanism of action of estrogens?

-steroid hormones like estradiol diffuse across the cell membrane after dissociation from their binding sites on sex hormone-binding globulin or albumin in the plasma, and bind with high affinity to specific nuclear receptor proteins

-the activated steroid-receptor complex interacts with nuclear chromatin to initiate hormone-specific RNA synthesis

-this results in the synthesis of specific proteins that mediate a number of physiologic functions

What are estrogens and androgens necessary for?

-conception

-embryonic maturation

-development of primary and secondary sexual characteristics at puberty

What are sex hormones used therapeutically for?

-contraception

-managementof menopausal symptoms

-replacement therapy in hormone deficiency

What are sex hormones synthesized from?

the precursor cholesterol

Estradiol

-the most potent estrogen produced and secreted by the ovary

-the principal estrogen in premenopausal women

Estrone

-a metabolite of estradiol that has approximately 1/3 the estrogenic potency of estradiol

-the primary circulating estrogen after menopause

Estriol

-metabolite of estradiol

-significantly less potent than estradiol

-present in significant amounts during pregnancy, because it is synthesized by the placenta

Ethinyl Estradiol

-synthetic estrogen

-undergoes less first-pass metabolism than do naturally occurring hormones

-effective when administered orally at lower doses

What are the therapeutic uses of estrogen?

-most frequently used for contraception and postmenopausal hormone therapy (HT)

-were widely used for prevention of osteoporosis

-due to risks associated with estrogen therapy, current guidelines recommend use of biphosphonates

Postmenopausal HT

-the primary indication for estrogen therapy in postmenopausal women in menopausal symptoms, such as vasomotor instability ("hot flashes" or "hot flushes"), and vaginal atrophy

-a common oral preparation used for the treatment of menopausal symptoms is conjugated equine estrogens which primarily contains sulfate esters of estrone and equilin

-other estrone-based oral preparations include esterified estrogens and estropipate

-transdermal preparations of estradiol are also effective in treating menopausal symptoms

What is used with estrogen therapy for women with an intact uterus?

-a progestogen is always included with the estrogen therapy, because the combination reduces the risk of endometrial carcinoma associated with unopposed estrogen

-women who have undergone a hysterectomy may use estrogen alone

What has use of HT been associated with?

-an increased risk of cardiovascular events and breast cancer

-HT should be prescribed at the lowest effective dose for the shortest possible time to relieve menopausal symptoms

Contraception

the combination of an estrogen and progestogen provides effective contraception via the oral, transdermal, or vaginal route

What are some other uses for estrogen?

-estrogen therapy usually in combination with a progestogen, is used to stimulate development of secondary sex characteristics in young women with primary hypogonadism

-replacement therapy is used for women who have hormonal deficiencies due to surgical menopause or premature ovarian failure

Synthetic Estrogens

-e.g. Ethinyl estradiol and Estradiol valerate

-are well absorbed after oral administration

-Estradiol valerate is a prodrug of estradiol which is rapidly cleaved to estradiol and valeric acid

-the synthetic estrogens are fat soluble, stored in adipose tissue, and slowly released

-these compounds have a prolonged action and a higher potency compared to the natural estrogens

What are the adverse effects of estrogens?

-breast tenderness

-thromboembolism

-nausea

-headache

-fluid retention

-hypertension

-myocardial infarction

Selective Estrogen Receptor Modulators (SERMs)

-e.g. Tamoxifen, Raloxifene, Clomiphene

-a class of estrogen-related compounds

-display selective agonism or antagonism for estrogen receptors depending on the tissue type

What is the mechanism of action of SERMs?

Tamoxifen and Raloxifene compete with estrogen for binding to the estrogen receptor in breast tissue

Raloxifene

-also lowers serum total cholesterol and low-density lipoprotein (LDL)

-acts as an estrogen agonist in bone, leading to decreased bone resorption, increased bone density, and decreased vertebral fractures

Clomiphene

-acts as a partial estrogen agonist and interferes with the negative feedback of estrogens on the hypothalamus

-this effect increases the secretion of gonadotropin-releasing hormone and gonadotropins, thereby leading to stimulation of ovulation

What are the therapeutic uses of Tamoxifen?

-currently used in the treatment of metastatic breast cancer

-as adjuvant therapy following masectomy or radiation for breast cancer

What are the therapeutic uses of Raloxifene?

-used as prophylactic therapy to reduce the risk of breast cancer in high-risk patients

-approved for the prevention and treatment of osteoporosis in postmenopausal women

What is the therapeutic use of Clomiphene?

used in the treatment of infertility

What are the adverse effects of Tamoxifen?

-the most frequent are hot flashes and nausea

-due to the estrogenic activity in the endometrium, endometrial malignancies have been reported with tamoxifen therapy

What are the adverse effects of Raloxifene?

-hot flashes and leg cramps are common adverse effects

-there is an increased risk of deep vein thrombosis and pulmonary embolism

What are the adverse effects of Clomiphene?

-headache, nausea, vasomotor flushes, visual disturbances, and ovarian enlargement

-increased risk of multiple gestation, usually twins

Progesterone

-natural progestogen

-produced in response to luteinizing hormone (LH) by both females and males

-it is also synthesized by the adrenal cortex in both sexes

What is the mechanism of action of Progesterone?

-in females, it promotes the development of a secretory endometrium that can accommodate implantation of a newly forming embryo

-the high levels of progesterone that are released during the second half of the menstrual cycle (the luteal phase) inhibit the production of gonadotropin and, 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 and reducing uterine contractions

-if conception does not take place, the release of progesterone from the corpus luteum ceases abruptly

-the decline in progesterone stimulates the onset of menstruation

What are the therapeutic uses of progestogens?

-the major clinical uses of progestogens are for contraception or hormone replacement therapy

-for both contraception and HT, progestogens are often used in combination with estrogens

-progesterone is not used as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability

-synthetic progestogens used for contraception are more stable to first-pass metabolism, allowing lower doses when administered orally

Synthetic Progestogens

-levonorgestrel, norethindrone, norethindrone acetate, and norgestrel

-Medtroxyprogesterone acetate is an injectable contraceptive

-also used for the control of dysfunctional uterine bleeding, treatment of dysmenorrhea, and management of endometriosis and infertility

What are the adverse effects of progestogens?

-headache

-depression

-weight gain

-changes in libido

Mifepristone

-an antiprogestin, a progesterone antagonist

-administration of this drug results in termination of pregnancy due to interference with the progesterone needed to maintain pregnancy

-Mifepristone is often combined with the prostaglandin analog misoprostol to induce uterine contractions

-the major adverse effects are abdominal pain, uterine bleeding, and the possibility of an incomplete abortion

Contraceptives

may be hormonal or nonhormonal

Combination Oral Contraceptives

-a combination of estrogen and progestin is the most common type of oral contraceptive

-the most common estrogen in combination pills is ethinyl estradiol

-some examples of most common progestins are norethindrone, norethindrone acetate, levonorgestrel

-these preparations are highly effective in achieving contraception

Transdermal Patch

-the contraceptive transdermal patch contain ethinyl estradiol and the progestin norelgestromin

-during the 28-day cycle, one patch is applied each week for 3 weeks to the abdomen, upper torso

-no patch is worn during the 4th week

-the transdermal patch has efficacy comparable to that of the oral contraceptives

Progestin Intrauterine Device

-various levonorgestrel-releasing intrauterine devices offer a highly effective method of contraception for 3-5 years

-should be avoided in patients with pelvic inflammatory disease or a history of ectopic pregnancy

Androgens

a group of steroids that have anabolic and/or masculinizing effects in both males and females

Testosterone

-most important androgen in humans

-synthesized by Leydig cells in the testes and in smaller amounts by thecal cells in the ovaries and by the adrenal gland in both sexes

-other androgens secreted by the testes are 5α-dihyrotestosterone (DHT), androstenedione, and DHEA in small amounts

-in adult males, testosterone secretion by Leydig cells is controlled by gonadotropin-releasing hormone from the hypothalamus, which stimulates the anterior pituitary gland to secrete FSH and LH

-testosterone or its active metabolite, DHT, inhibits production of these specific trophic hormones through a negative feedback loop and, thus, regulates testosterone production

What are androgens required for?

-normal maturation in the male

-sperm production

-increased synthesis of muscle proteins and hemoglobin

-decreased bone resorption

What is the mechanism of action of androgens?

-they bind to a specific nuclear receptor in a target cell

-after diffusing into the cells of the prostate, seminal vesicles, epididymis, and skin, testosterone is converted by 5α-reductase to DHT, which binds to the receptor

What are the therapeutic uses of androgens?

-androgenic steroids are used for males with primary or secondary hypogonadism

-can be used to treat chronic wasting associated with human immunodeficiency virus or cancer

-an unapproved use of anabolic steroids is to increase lean body mass, muscle strength, and endurance in athletes and body builders

-DHEA (a precursor of testosterone and estrogen) has been popularized as an anti-aging hormone as well as a "performance enhancer"

-Danazol, a weak androgen, is used in the treatment of endometriosis and fibrocystic breast disease

What are the adverse effects of androgens?

-weight gain

-acne

-decreased breast size

-deepening voice

-increased libido

-increased hair growth

What are the pharmacokinetics of testosterone?

-ineffective orally because of inactivation by first-pass metabolism

-administered via a transdermal patch, topical gel or solution, buccal tablet, or implantable pellet

-esters of testosterone (for example, testosterone cypionate or enanthate) are administered intramuscularly

-the esterified formulations are more lipid soluble and have an increased duration of action up to several weeks

-active metabolites of testosterone include DHT and estradiol

-inactive metabolites are excreted primarily in the urine

Testosterone Derivatives

-alkylation of the 17α position of testosterone is associated with less hepatic metabolism and allows oral administration of the hormone

-Methylestosterone and gluoxymesterone are examples of orally administered testosterone derivatives

What are the adverse effects of androgens in females?

-androgens can cause masculinization, acne, growth of facial hair, deepening of the voice, male pattern baldness, and excessive muscle development

-menstrual irregularities may also occur

-testosterone should not be used by pregnant women because of possible virilization of the female fetus

What are the adverse effects of androgens in males?

-excess androgen can cause priapism, impotence, decreased spermatogenesis, gynecomastia, and cosmetic changes such as those described for females

-androgens can also stimulate growth of the prostate

What are the general side effects of androgens?

-can increase serum LDL and lower serum HDL levels

-they may also cause fluid retention and peripheral edema

-testosterone replacement therapy has been associated with a possible increased risk of myocardial infarction and stroke

Antiandrogens

-e.g. Flutamide, Finasteride

-they counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors

-act as competitive inhibitors of androgens at the target cell and are effective orally for the treatment of prostate cancer

-Finasteride inhibits 5α-reductase, resulting in decreased formation of dihydrotestosterone

-these agents are used for the treatment of benign prostatic hyperplasia