ESTROGENS AND ANDROGENS

Sex hormones

Are necessary ofr conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty.

aromatization

is the last step in estrogen synthesis.

17β-estradiol

Estradiol is aka

estradiol

• is the most potent estrogen produced and secreted by the ovary.

• It is the principal estrogen in premenopausal women

Estrone

• is a metabolite of estradiol that has approximately one-third the estrogenic potency of estradiol.

• is the primary circulating estrogen after menopause, and it is generated mainly from conversion of androstenedione in peripheral tissues.

estriol

• metabolite of estradiol

• is significantly less potent than is estradiol.

• It is present in significant amounts during pregnancy, because it is the principal estrogen produced by the placenta

Estrone and equilin

is an oral preparation used for hormone replacement therapy

equilin

obtained from urine of pregnant mares

Ethinyl estradiol

• Synthetic estrogen

• undergo less first-pass metabolism than do naturally occurring steroids and, thus, are effective when administered orally at lower doses

Selective estrogen receptor modulators (SERMs)

Nonsteroidal compounds that bind to estrogen receptors and exert either estrogenic or antiestrogenic effects on target tissues are called

Genomic (main)

• Enters cell → binds nuclear estrogen receptor → hormone-receptor complex binds DNA → increase RNA transcription → increase protein synthesis → long-term effects

Nongenomic (rapid)

• Binds membrane receptors → activates G-protein/second messengers → vasodilation via nitric oxide and prostacyclin

Estrogens MOA

Estrogens

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

• were previously widely used for prevention of osteoporosis, but current guidelines recommend use of other therapies such as alendronate

• used for replacement therapy in premenopausal patients who are deficient in this hormone

• Hypogonadism

• Premature menopause

• Surgical menopause

Estrogen deficiency can be due to

estrogen therapy

primary indication for ____ in postmenopausal women is menopausal symptoms, such as vasomotor instability (for example, “hot flashes” or “hot flushes”) and vaginal atrophy

Progestogen + estrogen therapy

Postmenopausal HT for women who have an intact uterus because this combination reduces the risk of endometrial carcinoma

Unopposed estrogen therapy

In postmenopausal HT for women who have undergone a hysterectomy, this is recommended because progestins may unfavorably alter the beneficial effects of estrogen on lipid parameters

less

estrogen used in replacement therapy is substantially ____ than the doses used in oral contraception. Thus, the adverse effects of estrogen replacement therapy are usually less pronounced than those seen in women taking estrogen for contraceptive purpose

Estradiol by transdermal patch or gel

also effective in treating postmenopausal symptoms.

true

Due to concerns over the risks of HT (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

TRUE OR FALSE

Vaginal estrogen

For postmenopausal HT in women who only have urogenital symptoms, such as vaginal atrophy, this is used as treatment rather than systemic estrogen

Estrogen + progestogen

Combination of estrogen and this is effective for contraception via oral, transdermal or vaginal route

Estrogen + progestogen

• Instituted to stimulate development of secondary sex characteristics in young women with primary hypogonadism

• used for women who have premature menopause or premature ovarian failure.

true

Naturally occurring estrogens are readily absorpbed through the GI, skin, and mucous membranes

True or false

Micronized estradiol

Estradiol when taken orally is rapidly metabolized and partially inactivated. Therefore ___ is available and has better bioavailability

• Ethinyl estradiol

• Mestranol

• Estradiol valerate

Synthetic estrogen analogs include

Mestranol

This synthetic estrogen is quickly demethylated to ethinyl estradiol, which is metabolized more slowly than the naturally occurring estrogens by the liver and peripheral tissues.

Estradiol valerate

This synthetic estrogen is rapidly cleaved to estradiol and valeric acid. Being fat soluble, they are stored in adipose tissue, from which they are slowly released

Synthetic estrogen analogs

Which have prolonged action and higher potency? Synthetic estrogen analogs or natural estrogens

Serum albumin or sex hormone-binding globulin

Estrogens are transported in the blood bound to

Transdermal, intravaginally, injection

Estrogens route of administration to reduce first pass metabolism

• Nausea

• Breast tenderness

• Thromboembolism

• Myocardial infarction

• Breast and endometrial cancer

• hypertension

• Peripheral edema

Adverse effects of estrogen therapy

Selective estrogen receptor modulators (SERMs)

are a class of estrogen-related compounds that display selective agonism or antagonism for estrogen receptors depending on the tissue type

progestogen

The increased risk of endometrial cancer can be offset by including a this along with the estrogen therapy

SERMs

• Tamoxifen

• Toremifen

• Raloxifene

• Clomiphene

• Ospemifene

are a class of estrogen-related compounds that display selective agonism or antagonism for estrogen receptors depending on the tissue type.

• Tamoxifen

• Toremifene

• Raloxifene

SERMs that compete with estrogen for binding to the estrogen receptor in breast tissue.

estrogen

Stimulates normal breast growth

Raloxifene

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

• Does not have appreciable estrogen receptor agonist acitivity

• Does not predispose to endometrial cancer

• Lowers serum total cholesterol and low-density lipoprotein

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

tamoxifen

• currently used in the treatment of metastatic breast cancer

• adjuvant therapy following mastectomy or radiation for breast cancer

Tamoxifen and raloxifene

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

raloxifene

approved for the prevention and treatment of osteoporosis in postmenopausal women

Clomiphene

useful for the treatment of infertility associated with anovulatory cycles

Ospemifene

indicated for the treatment of dyspareunia (painful sexual intercourse) related to menopause

true

SERMs are rapidly absorbed after oral administration

True or false

Raloxifene

This SERM is rapidly converted to glucuronide conjugates through first-pass metabolism. These agents undergo enterohepatic cycling, and the primary route of excretion is through the bile into feces.

tamoxifen

This SERM is extensively metabolized by cytochrome P450 isoenzymes, including formation of active metabolites via the CYP3A4/5 and CYP2D6 isoenzymes.

• Hot flashes

• Nausea

Tamoxifen therapy

• Endometrial hyperplasia

• Malignancies

Tamoxifen and toremifene adverse effects

• Hot flashes

• Leg cramps

• Increased risk of deep vein thrombosis

• Pulmonary embolism

• Reitnal vein thrombosis

Raloxifene adverse effect

Cholestyramine

can significantly reduce the absorption of raloxifene, and concurrent use should be avoided

Clomiphene

This SERM increase the risk of multiple births (twins or tiplets)

• Headache

• Nausea

• Vasomotor flushes

• Visual disturbances

• Ovarian enlargement

Clomiphene adverse effects

progesterone

is produced in response to luteinizing hormone (LH) by both females (secreted by the corpus luteum, primarily during the second half of the menstrual cycle, and by the placenta) is produced in response to luteinizing hormone (LH) by both females (secreted by the corpus luteum, primarily during the second half of the menstrual cycle, and by the placenta)

Progesterone

In females, this promotes the development of a secretory endometrium that can accommodate implantation of a newly forming embryo

Progesterone

This inhibit the production of gonadotropin and, therefore, prevent further ovulation.

• If conception takes place, this continues to be secreted, maintaining the endometrium in a favorable state

• If it does not take place, the release of this ceases abruptly, stimulating onset of menstruation

• Contraception

• Hormone deficiency treatment

Major clinical uses of progestogens

estrogen

For contraception, progestogens are used in combination with

progestins

This is a synthetic progestogen used in contraception that are more stable to first pass metabolism allowing lower doses

• Desogestrel

• Dienogest

• Drospirenone

• Levonorgestrel

• Norethindrone

• Norethindrone acetate

• Norgestimate

• Norgestrel

Synthetic progestogens include

Medroxyprogesterone acetate

an injectable contraceptive, and the oral form is a common progestin component of postmenopausal HT

Progesterone used in

• Control of dysfunctional uterine bleeding

• Dysmenorrhea

• Management of endometriosis and infertility

true

micronized preparation of progesterone is rapidly absorbed after oral administration. It has a short half-life. Synthetic progestins are less rapidly metabolized

True or false

Medroxyprogesterone acetate

• This progestogen has a half life of 30 days

• If injected IM or SC, it has a half-life of about 40-50 days

• Procvides contraceptive activity for approx. 3 months

• Headache

• Depression

• Weight gain

• Changes in libido

Progestins adverse effect

• Norethindrone

• Norethindrone acetate

• Norgestrel

• Levonorgestrel

Progestins that are derived from 19-nortestosterone

• Androgenic activity

• Acne

• hirsutism

Progestins that are derived from 19-nortestosterone has adverse effects such as

Norgestimate and drospirenone

Less androgenic progestins that are preferred in women with acne

Drospirenone

progestogen that may raise serum potassium due to antimineralocorticoid effects and concurrent use with other drugs that increase potassium

This progestogen ka

Mifepristone

• progesterone antagonist with partial agonist activity.

• Administration of this drug to females early in pregnancy usually results in abortion of the fetus due to interference with the progesterone needed to maintain pregnancy

Mifepristone + misoprostol

• Antiprogestin that induces uterine contraction.

• Major adverse effects:

  • Significant uterine bleeding

  • Incomplete abortion

Interference with ovulation

Most common pharmacologic intervention for prevention of pregnancy

1. Combination oral contraceptives

2. Transdermal patch

3. Vaginal ring

4. Progestin-only pills

5. Injectable progestin

6. Progestin implants

7. Progestin intrauterine device

8. Postcoital contraception

Major classes of contraceptives

Estrogen and progestin

• Combination oral contraceptive

• Are the most common type of oral contraceptives

• Are monophasic combination pills given over 21 to 24 days

Triphasic oral contraceptive product

• Combination oral contraceptive

• Attempt to mimic the natural female cycle and most contain a constant dose of estrogen with increasing doses of progestin over 3 successive 7 day period

Estradiol valerate + dienogest

• Combination oral contraceptive

• Four-phasic oral contraceptive

true

Most oral contraceptives, active pills are taken for 21 to 24 days followed by 4 to 7 days of placebo, for a total regimen of 28 days

True or false

Withdrawal bleeding

When taking oral contraceptives, this occurs during the hormone-free (placebo) interval

Ethinyl estradiol

Most common estrogen in the combination pills

• Norethindrone

• Norethindrone acetate

• Levonorgestrel

• Desogestrel

• Norgestimate

• Drospirenone

Most common progestins

Extended-cycle contraception

Use of this type of oral contraception (84 active pills followed by 7 days of placebo) results in less frequent withdrawal bleeding

Ethinyl estradiol + norelgestromin

• Transdermal patch contraceptives contains these

• One contraceptive patch is applied each week for 3 weeks to the abdomen, upper torso, or buttock

• No patch is worn during the 4th week and withdrawal bleeding occurs

Transdermal patch

This type of contraceptive has efficacy comparable to that of the oral contraceptives, but is less effective in women weighing greater than 90 kg

Transdermal patch

• Total estrogen exposure of this type of contraceptive may be significantly greater than that seen with oral contraceptive

• Increased exposure to estrogen increases risk of thromboembolism

Ethinyl estradiol + etonogestrel

• Vaginal ring contains these

• Ring is inserted into the vaginal and is left in place for 3 weeks and then removed

• No ring is used during the fourth week, and withdrawal bleeding occurs

• Contraceptive vaginal ring has efficacy, contraindications, and adverse effects similar to oral contraceptives

Norethindrone

• Contains progestin only, usually ___

• Called mini-pill, taken daily on continuous schedule

Progestin-only pills

• This type of contraceptive deliver low, continuous dosage of drug.

• This preparation are less effective than combination product, and may produce irregular menstrual cycles more frequently

• Used for patients wo are BREAST-FEEDING, are INTOLERANT TO ESTROGEN, are SMOKERS, or have OTHER CONTRAINDICATIONS to estrogen-containing products

Medroxyprogesterone acetate

• Injectable progestin

• Administered via IM or SC injection every 3 months

• Weight gain is common adverse effect

• provides high sustained levels of progestin, thus many women experience amenorrhea

• Return to fertility may also be delayed for several months after discontinuation

• May contribute to bone loss and predispose patients to osteoporosis or fractures

• Drug should not be continued for more than 2 years

Etonogestrel

• Progestin implant

• Offers contraception for approx. 3 years

• Implant is nearly as reliable as sterilization, and the effect is totally reversible when surgically removed

• Adverse effects:

  • Irregular menstrual bleeding

  • Headaches

• Has not been studied in women who way more than 130% of ideal body weight, may be less effective in this population

Levonorgestrel-releasing intrauterine system

• Progestin intrauterine device

• Offers a highly effective method of contraception for 3-5 years depending on the system

• For women who desire long-term contraception and those who have contraindication to estrogen therapy

• Avoided in px with pelvic inflammatory disease or history of ectopic pregnancy

Postcoital contraception

• Reduces the probability of pregnancy after an episode of coitus without effective contraception to between 0.2% and 3%

• Should be taken ASAP after unprotected intercourse and preferably within 72 hours

• Progestin-only are generally better tolerated than estrogen-progestin combination regimens

• Levonorgestrel (preferred)

• Ethinyl estradiol + levonorgestrel

• Emergency contraception/post coital contraception uses high doses of

ulipristal

• Alternative emergency contraceptive is the progesterone agonist/antagonist ___

• Indicated for emergency contraception within 5 days of unprotected intercourse

estrogen

provides a negative feedback on the release of LH and follicle-stimulating hormone (FSH) by the pituitary gland, thus preventing ovulation

Progestin

• also thickens the cervical mucus, thus hampering the transport of sperm

• Withdrawal stimulates menstrual bleeding during the placebo week.

Estrogen

Most common adverse effect of this includes

• Breast fullness

• Fluid retention

• Headache

• Nausea

• Increased BP

Progestins

may be associated with depression, changes in libido, hirsutism, and acne.

Oral contraceptives

Adverse effect of this type of contraceptive include

• thromboembolism

• thrombophlebitis

• myocardial infarction

• stroke

Adverse effects are most common in women who are over age 35 and smoke

• Are associated with a decreased risk of cervical and ovarian cancer

Contraindicated in

• Cerebrovascular and thromboembolic disease

• Estrogen dependent neoplasms

• Liver disease

• pregnancy

Combination oral contraceptives

This type of contraceptives should not be used in patients over the age of 35 who are heavy smokers

State probability of pregnancy after unprotected intercourse

• 3 days before ovulation: 15%

• 1 or 2 days before ovulation: 30%

• day of ovulation: 12%

• 1 or 2 days after ovulation: near zero

State probability of pregnancy after unprotected intercourse

• 3 days before ovulation:

• 1 or 2 days before ovulation:

• day of ovulation:

• 1 or 2 days after ovulation: