508 Lecture 2: Pharmacology of Sex Hormones

What drug classes are related to sex hormones?

• Direct replacement hormones

  • Estrogens

  • Progestagens

  • Androgens

  • Oral contraceptives, hormone replacement therapy for women and men

• Upstream regulatory agents

  • Gonadotropins

  • GnRH agonists and antagonists

• Downstream modifiers

  • Aromatase inhibitors

  • Selective estrogen receptor modulators

  • Antiandrogens

What are the hormonal methods for contraception?

• Daily combined estrogen + progesterone oral contraceptive pills

• Daily progestin-only oral contraceptive pills (POPs)

• Transdermal weekly patches

• Long-term hormonal intrauterine devices (IUDs)

What is the mechanism of action of oral contraceptives?

Three-pronged approach:

• 1) suppression of ovulation

• 2) change turbidity of cervical mucus, and

• 3) altering the endometrium

Highly effective (9% failure rate)

What are indications for oral contraceptives?

• Contraception/birth control

• Menstrual pain

• Irregular menstruation

• Fibroids

• Endometriosis-related pain

• Menstrual-related migraines

• Acne, hirsutism

The estrogen component of oral contraceptives can be…?

Estradiol, Ethinylestradiol, or Estetrol

What is the importance of the C-17 position of ethinylestradiol?

• The C-17 position makes ethinylestradiol orally available

Is the progestin component of oral contraceptives natural or synthetic?

They contain synthetic forms only in order to provide stable 24hr hormone levels

• Natural forms are not stable, natural progesterone breaks down too quickly

What are the 1st generation progestins?

• Norethindrone

• Ethinyl diacetate

• Norgestrel

• Norethindrone acetate

Which generation progestins have both estrogenic and androgenic activity? What is the downside of this?

• 1st Generation progestins has both effects

• This means that it has a larger array of adverse effects

What is the mechanism of action of combination oral contraceptives?

• Suppress LH and FSH

• Absence of mid-cycle LH surge

• Prevent ovulation

• The combination acts synergistically and consistently

What is the role of estrogens in MOA of oral contraceptives?

• Primary function → stabilize endometrial lining and provide menstrual cycle control

• Estrogens suppress FSH release from the pituitary; hence a follicle cannot begin development

  • This may contribute to blocking LH surge and preventing ovulation

What is the role of progestins in MOA of oral contraceptives?

• Progestins provide the main contraceptive effect

• Progestins bind to PR receptors in the cells of the cervix leading to production of thick mucus, which prevents sperm penetration, slowing transport through the fallopian tube

• Progestins bind to PR receptors in the uterine lining and counteract proliferative signals of E2, leading to thinning and atrophy of endometrium

• Progesterone diminishes the frequency of GnRH pulses in the hypothalamus in the brain using negative feedback loop, thus blocking LH surge and preventing ovulation

In oral contraceptives, which component (estrogen or progestin) provides the main contraceptive effect?

Progestins

Progestins bind to PR receptors in which two locations?

• 1) Bind to PR receptors in the cervix → leads to production of thick mucus → prevents sperm penetration → slows transport through fallopian tube

• 2) Bind to PR receptors in the uterine lining and counteracts proliferative signals of E2 → leads to thinning and atrophy of endometrium

What is the most common type of birth control pill?

Combined monophasic

• One concentration of estrogenic component

• One concentration of progestin component

Ex: Yasmin (Berlex) - 30mcg ethinylestradiol + 3mg drospirenone

What are absolute/relative contraindications to oral contraceptives?

ABSOLUTE CONTRAINDICATIONS

✓ Heart attack, stroke, history of coronary artery disease or history of blood clots

✓ Tumors of the liver or impaired liver function

✓ Known or suspected cancer of the breast or reproductive system

✓ Known or suspected pregnancy

✓ Migraines

✓ Smokers

✓ Unmanaged hypertension

Relative

• Diabetes or strong family history of diabetes

• Gallbladder disease including having your gallbladder removed

• Acute mononucleosis

• Sickle cell disease

• Undiagnosed abnormal vaginal bleeding

True or False: It is recommended that IUDs and contraceptive implant be offered as first-line methods of contraception to all women, inlcuding adolescents

True

What are the two different types of long-acting reversible contraception (LARCs)?

Hormonal and non-hormonal intrauterine devices (IUDs) and subdermal implants

What are examples of nonhormonal and hormonal LARC?

Nonhormonal

• IUD Paragard– spermicidal non-hormonal copper-containing device; 10 years of use; may increase bleeding

Hormonal

• IUDs and subdermal - prevent pregnancy by thickening cervical mucus, thinning the uterine wall, and partially stopping ovulation

• IUDs Milena and Liletta– contain 52 mg of progestin levonorgestrel; 5 years of use; inhibits ovulation, thickens cervical mucus;

reduces heavy bleeding

• IUD Kyleena– contains 19.5 mg of levonorgestrel; 5 years of use

• IUD Skyla– contains 13.5 mg of levonorgestrel; 3 years of use

• Subdermal implant Nexplanon - slowly releases the progestin etonogestrel, it contains barium to facilitate the radiologic detection of implants that cannot be palpated; 3 years of use; inhibits ovulation, thickens cervical mucus

What is perimenopause and symptoms of menopausal transition?

• Perimenopause: a period preceding to menopause (2-8 years)

  • Sharp decline in ovarian mass and fertility after age 35 and on

  • Irregular hormone secretion

• Menopausal transition can cause hot flashes, night sweats, irregular bleeding, and vaginal dryness, sleep disturbances, mood swings, depression, impaired memory, incontinence, sexual dysfunction

What is hormone replacement therapy (HRT) for women?

Taking medications containing female hormones to replace the ones the body no longer makes after menopause

Estrogen based HRT is primarily used for?

Used for tx of vasomotor and urogenital symptoms of menopause + prevention of osteoporosis

When should progestin be added to HRT?

Progestin should be added for protection of uterine endometrium, as it reduces risk of endometrial hyperplasia and carcinoma

*Those who have undergone hysterectomy take only estrogen

What are benefits of HRT?

• Symptom relief: reduces hot flashes/night sweats, improves vaginal health, stabilizes mood, improves sleep quality

• Bone health

• Potentially has cardiovascular benefits

• Potentially improves bladder function, prevents memory loss, helps maintaining muscle mass

What are risks of HRT?

• Endometrial (uterine) cancer

• Venous thromboembolism

• Breast cancer *

• Gallbladder disease

What is testosterone replacement therapy (TRT) for men used for?

Hypogonadism - gradual decrease of free testosterone with age

• Results in sexual dysfunction, obesity, fatigue, loss of muscle mass, loss of body hair, depression

What is primary vs secondary hypogonadism?

• Primary hypogonadism: the testicular steroidogenesis is insufficient to synthesize adequate levels of testosterone

• Secondary hypogonadism: signaling to the testis is unable to stimulate sufficient testosterone production by Leydig cells

What are goal testosterone levels in elderly men vs young men?

Elderly: 500-800 ng/mL

Young men: 600-900 ng/mL

What are dosage forms of TRT?

oral, buccal, and transdermal gels, patches, solutions, subcutaneous pellets, pills, intramuscular injections, intranasal gels

What are contraindications of TRT?

• History of breast cancer, prostate cancer

• Uncontrolled heart failure

• Untreated obstructive sleep apnea,

• A pre-treatment hematocrit over 48%

• Palpable undiagnosed prostate nodules

• An elevated prostate specific antigen (PSA)

• Having a first-degree relative with prostate cancer

What are our upstream regulatory agents?

Gondaotropins and GnRH agonist/antagonists

What are gonadotropins used for? What types are there?

• Treatment of infertility

• Ovulation induction in IVF

• Testosterone production and sperm development

• Human menopausal gonadotropin (hMG)

  • From urine of postmenopausal women

  • A mixture of FSH and LH

• Human chorionic gonadotropin (hCG)

  • From urine of pregnant women

  • Mostly LH, little FSH (good for stimulation of T in Leydig cells)

• FSH products

  • Follitropins, synthetic recombinant FSH

What is the main use of GnRH agonists?

Metastatic prostate cancer

What are GnRH (LHRH) agonists mechanism of action?

• First phase: activation

  • Initially GnRH agonists promote LH and FSH →

• Second phase: After longer exposure to the drugs (10 days) the receptors undergo desensitization and internalization

• This leads to decrease in FSH and LH, which is the therapeutic goal of this treatment

What is Goserelin (Zoladex)?

• Injectable gonadotropin releasing hormone agonist

• Used to suppress production of the sex hormones (testosterone and estrogen) in the treatment of breast and prostate cancer as well as endometriosis

  • Side effects: tumor flare effect, bone pain, hot flushes, headache, stomach upset, depression, difficulty urinating, weight gain, swelling and tenderness of breasts, decreased erections and reduced sexual desire

What are the main uses of GnRH antagonists?

• IVF (in vitro fertilization) procedure

• Used against advanced prostate cancer

• Fibroids/endometriosis

What is the MOA of GnRH antagonists?

• Competitively and reversibly bind to GnRH receptor

• Block LH and FSH release from the pituitary

• Robustly suppress T in men

• Suppress E2 and P4 in women

GnRH antagonists block release of what from where?

Block LH and FSH release from the pituitary

What are our downstream modifiers?

• Aromatase inhibitors

• Selective estrogen receptor modulators

• Antiandrogens

What is the role of aromatase?

Aromatase is an enzyme that converts androgens (testosterone) to estrogens

Therefore, aromatase inhibitors block the conversion of testosterone to estrogen

Are aromatase inhibitors reversible or irreversible?

Both!

• Irreversible → Form permanent bond with the enzyme (example: Exemestane (Aromasin)

• Reversible → Inhibit estrogen synthesis by completion with aromatase

What are SERMs? What are the used for?

Selective estrogen receptor modulators

SERMs as treatment

SERMs as treatment → Generally, used to prevent and/or treat estrogen-related diseases/disorders

• Breast cancer (tamoxifen)

• Gynecomastia (tamoxifen)

• Postmenopausal osteoporosis (raloxifene

What do antiandrogens do?

Antiandrogens inhibit circulating androgens (testosterone) by:

• 1) blocking androgen receptors and

• 2) suppressing androgen (testosterone) synthesis, or acting in both those ways

What are antiandrogens commonly used for?

Hirsutism and prostate cancer