Drugs targeting the HPG Axis - lecture 29

drugs we need to know

drugs we need to know

endocrine physiology

endocrine physiology

Hormone Transport

Circulate Freely or Bound

Sex hormone-binding globulin (SHBG)- regulates availability and activity in body

Feedback Mechanism

regulates sex hormones availability and activity in body

Removal of Hormone from Circulation

Metabolic Transformation

- liver(main site), periphery

Metabolic Clearance

- undergo urinary secretion, liver, saliva, sweat, brain

Gonadotropic Hormones GnRH, LH, FSH

Gonadotropic Hormones GnRH, LH, FSH

Gonadotropin-releasing hormone (GnRH)

pulsatile secretion

Cyclical secretion luteinizing hormone (LH), follicle-stimulating hormone (FSH)

females

ovary

LH: ovulation, corpus luteum

FSH: dvpt follicle, estradiol and progesterone

males

testes

LH: Leydig cells: testosterone

FSH: Sertoli cells: spermatogenesis

positive

Preovulatory surge of estrogen: ___________ feedback.

negative

Androgens and estrogens: ___________ feedback

Inhibin

negative feedback on FSH secretion by the pituitary

Hormone Receptor GnRH, LH, FSH - MOA

G protein-coupled receptor (GPCR) - cell surface membrane receptor

Hormone released from the hypothalamus or pituitary binds to its receptor expressed on the cell membrane of targeted organ

Signal transduction

Can activate or repress gene transcription

Binding of hormone to its receptor leads to synthesis and secretion of hormones

GnRH Agonists

GnRH is normally secreted in pulsatile manner.

Stimulating FSH and LH release in a non pulsatile manner causes continuous stimulation of the gonadtrophs receptors and causes down-regulates GnRH receptors on gonadotrophs (clinical use).

GnRH agonists uses

Palliative therapy and treatment of advanced prostate cancer and premenopausal hormone receptor-positive (HR+) advanced breast. Avoid premature LH surge (ovulation) in in-vitro fertilization (IVF protocols)

Suppress/delay puberty in gender-questioning and transgender youth (off-label)

Suppress steroid-responsive condition: endometriosis, uterine fibroids, acute intermittent porphyria, priapism

Pharmacological castration (e.g., precocious puberty)

Test hypothalamic vs. pituitary defects in diagnoses of hypogonadotropic hypogonadism (HH) : measurement of LH and FSH secretion before/after GnRH drug administration

goserelin (Zoladex)

MOA - agonists at the GnRH receptor (GPCR receptor) continued receptor occupancy by goserelin, however, ultimately causes a down-regulation of production of LH and FSH and a resultant decrease in testosterone and estrogen levels (desensitization of GnRH receptor)

Initial stimulates production of LSH and FSH which in turn stimulates synthesis and secretions of sex hormones, testosterone and estrogen in a non-pulsatile manner. The non-pulsatile release of sex hormones causes disruption of the endogenous hormonal feedback systems, causing downregulations of GnRH receptor resulting in the down-regulation of testosterone and estrogen production.

Other GnRH agonist: leuprolide (Lupron) and triptorelin (Decapeptyl)

GnRH Agonists - goserelin (Zoladex)

Adverse Effects: bone pain, hot flashes, sweating, decreased bone density, decreased libido, dizziness, vertigo, insomnia, headaches

-- Females: Typical symptoms of menopause: depression, generalized pain, vaginal dryness might occur

-- Males: erectile dysfunction

Therapy in non-life-threatening diseases (e.g. endometriosis, uterine fibroids) typically limited to six months.

Drug Interactions: decreases efficacy of androgen therapy

Contraindications: pregnancy, breast-feeding, osteoporosis, undiagnosed abnormal vaginal bleeding

ganirelix (Antagon, Cetrorelix, Cetrotide) - GnRH Antagonists

Uses: Inhibit premature (LH) surges in women undergoing ovarian hyperstimulation with FSH and human chorionic gonadotropin (hCG), followed by subsequent Assisted Reproductive Technology (ART) procedures.

Mechanism of Action: antagonists at the GnRH receptor (GPCR)

Administer subcutaneously during certain phases of fertility (mid to late follicular phase of menstrual cycle. Inhibits the secretion of LH>>FSH in a dose dependent manner.

Adverse effects: nausea and headaches, anaphylaxis.

Contraindications: primary ovarian failure, pregnancy, breast feeding

Androgen

Estrogen

Progesterone

Androgen

Estrogen

Progesterone

synthesis

synthesis

Nuclear Receptor Androgens, Estrogen - MOA

Function as molecular switches in response to hormone binding

Hormone diffuses through the cell membrane binds to receptor in the cytoplasm

The hormone bound receptor can now travel to the nucleus through a nuclear pore

The hormone bound receptor binds to its hormone receptor element (HRE) located on DNA

Binding of the hormone bound receptor to HRE leads to modulation of gene transcription

Mechanism of Action (MOA): Enzyme Inhibitor

Mechanism of Action (MOA): Enzyme Inhibitor

male androgens

Leydig cells of the testes

Adrenal gland

female androgens

Theca cells of the ovarian follicle

Adrenal gland

Androgens Regulation – Feedback Loop

Androgens Regulation – Feedback Loop

Treatable Conditions

Male hypogonadism: develop or maintain secondary sex characteristics

Prostate Cancer

Male Pattern Baldness

Gender Transition

Adult Male Hypogonadism S/S

Infertility

Small prostate and testes

Gynecomastia

Adolescent Male Hypogonadism S/S

Delayed onset of puberty

Lack of facial or body hair development

Shortness of stature

Underdeveloped testicles and penis

Methyltestosterone (Covaryx) - testosterone analog

Testosterone Replacement Therapy Delivery Methods

Transdermal patch containing testosterone esters is applied each night to your back, abdomen, upper arm or thigh

Injections are given in a muscle

Gel rubbed into skin on upper arm or shoulder, or apply with an applicator under each armpit, or pump on your inner thigh - potential side effect: the possibility of transferring the medication to another person avoid skin to skin contact until gel is dried

Gum and cheek (buccal cavity) small putty-like substance delivers testosterone through the natural depression above your top teeth where your gum meets your upper lip (buccal cavity)

Implantable pellets testosterone containing pellets surgically implanted under the skin and need to be placed every three to six months

Orally – not recommended for long-term hormone replacement because it might cause

liver problems (1st pass). Monitoring for both beneficial and deleterious effects are required for all therapeutics

flutamide (EVLEXIN) - Androgen Receptor Antagonist

Uses:

in conjunction with GnRH analogs to treat metastatic prostate cancer

Treatment for Hirsutism in women (due to hepatoxicity should not be used for cosmetic purposes)

finasteride (Proscar, Propecia) - 5a-dihydrotestosterone (DHT) Synthesis Inhibitor

5a-reductase inhibitor

Used to treat benign prostatic hypertrophy and male patterned baldness

Use in women: Treatment for polycystic ovary syndrome (PCOS)

Contraindicated for women of childbearing age: Can cause birth defects in male children

dutasteride (Avodart)

Used to treat benign prostatic hypertrophy and male patterned baldness

Androgens: Side Effects

Potential Side Effects of Excessive Androgen Treatment

Reduced spermatogenesis and fertility due to feedback inhibition of LH and FSH secretion from anterior pituitary

Acne, particularly in women due to androgen stimulation of sebaceous glands beneath skin

Virilization (including facial hair and hirsutism) in women and children

In older men, increased risk of benign prostate hyperplasia and prostate cancer

Hepatotoxicity ( for testosterone derivatives )

National Institute on Drug Abuse (NIDA)

Steroid abuse disrupts the normal production of hormones in the body, causing both reversible and irreversible changes.

Anabolic steroid abuse has been associated with a wide range of adverse side effect

male estrogens

17 b-estradiol (estradiol)

Produced by the Leydig cells and in adipose tissues

Growth spurt, skeletal maturation, epiphyseal plate closure, maturation of sperm

female estrogens

17 b-estradiol (estradiol)

principal estrogen premenopausal

Estrone

primary circulating estrogen post menopause

Estriol

Principal estrogen produced by the placenta

Development of female sex organs and secondary sex characteristics, regulate menstrual cycle, skeletal maturation, mood, neuroprotection

Therapeutic Uses of Estrogens

Postmenopausal Hormonal Therapy

Oral Contraceptives

Primary Hypogonadism

Suppress ovulation in patients with intractable dysmenorrhea or hirsutism

Fertility Treatments

Gender Transition

review

review

ethinyl estradiol, agonist at the estrogen receptor

(Progestin – medroxyprogestrone) - Hormone Replacement Therapy (HRT)

Usually occurs in late 40s, early 50s

Estrogen and progesterone levels decline

Since estrogen plays other roles within the body, other systems are affected

symptoms of menopause:

-Hot flashes

-Changing sleep patterns

-Emotional changes (mood swings)

-Headaches

-Heart Palpitations

-Generalized Itching

Therapeutic Estrogens

Side effects :

Nausea, fluid retention, breakthrough bleeding, change in menstrual flow, breast tenderness.

Adverse Effects:

Thrombolytic complications; endometrial carcinoma; breast carcinoma; and hypertension.

In men feminization of genitalia & impotence.

contraindications:

Pregnancy, incomplete bone growth, undiagnosed genital bleeding; stroke, thrombophlebitis, or thromboembolic disease, heart disease.

Women with family history of breast or uterine cancer (BRCA gene)

Drug Interactions:

decrease efficacy of hypoglycemic agents

increase adverse effects of tricyclic antidepressants

herbal supplement - St. John's wort may cause loss of contraceptive or hormonal-replacement efficacy of estrogens

SERMs - Selective Estrogen-Receptor Modulators

display selective agonism or antagonism according to different tissues

Selectivity is possible because:

-- Estrogen receptors (ER), ER-a and ER-b show differential tissue expression

-- Tissue dependent responses ranging between pro-estrogenic, partially estrogenic and anti-estrogenic effects

Therapeutic Uses:

- Cancer Chemotherapy

- Prevent and treat osteoporosis

- Fertility

Selectivity is possible because:

- Estrogen receptors (ER), ER-a and ER-b show differential tissue expression

- Tissue dependent responses ranging between pro-estrogenic, partially estrogenic and anti-estrogenic effects

tamoxifen - SERMs Selective Estrogen-Receptor Modulators

display selective agonism or antagonism according to different tissues

Cancer Chemotherapy

clomiphene also clomifene – SERMs Selective Estrogen-Receptor Modulators

Fertility induction of ovulation in women with an intact hypothalamic-pituitary-ovarian axis

-- Oppose the negative feedback effects of endogenous estrogen. Increases GnRH and therefore increases the amplitude of the LH and FSH pulses.

Adverse effects: multiple births, ovarian cysts

Used off-label by men to treat both male infertility and secondary hypogonadism because it increases serum testosterone levels.

Abused by health athletes for performance enhancement

second gen - not in red

second gen - not in red

bazedoxifene (Duavee): - third generation

Approved in 2013, marketed in 2014 as a combination therapy with estradiol for the treatment of postmenopausal osteoporosis.

First modern HRT therapy without a progestin for postmenopausal women with an intact uterus – reduced risk of breast tenderness compared to traditional HRT.

fulvestrant - Anti-Estrogens

ICI 182,870 (FASLODEX)

- pure estrogen antagonist

- effective in treating tamoxifen-resistant tumors

letrozole (Femara) - Estrogen Synthesis Inhibitors

aromatase inhibitor

anastrozole (Arimidex)

Specifically block the local production of estrogens in hormonally-responsive tissues.

Uses:

- Second-line treatment for breast cancer in patients whom tamoxifen therapy is unsuccessful, but new studies rapidly proving its efficacy and promoting earlier use

- Aromatase inhibitors do not have the bone protecting activity of tamoxifen, and adjuvant therapies to prevent bone loss are in trials

letrozole

moa of ...

male progesterone

Produced in response to LH

Secreted by the testes and adrenal gland

female progesterone

Produced in response to LH

Secreted by the corpus luteum, placenta and adrenal gland

birth control - progestins

Make it difficult for sperm to reach egg by thicken cervical mucus and thin the uterine lining

Prevent ovulation, but not consistently

Prevent the egg from fully developing

Make it harder for a fertilized egg to attach to the uterine lining

Menstrual Cycles - progestins

Regulate menstrual cycles (start and stop menstrual cycle, amenorrhea)

other conditions - progestins

Help maintain pregnancies (during low progesterone production)

Counteracts estrogen effect on thickening of the uterine lining during HRT

Treat pain related to endometriosis

Stimulate appetite in AIDS or cancer patients DS or cancer

Progestins – Therapeutic Progesterone

Naturally occurring progesterone (low oral bioavailability

Synthetic progestins

19-nor testosterone derivatives display primarily progestational rather than androgenic activity

Estrane family – first generation

norethindrone; norethindrone acetate

Gonane family - second and third generation

replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are more potent progestins and less androgenic: norgestrel, levonorgestrel, drospirenone (antiandrogenic, anti-mineralocorticoid)

Uses: HRT - Formulations

Early HRT used estrogen alone: increased risk of uterine (endometrial) cancer. As a result, addition of progestin is now used to limit endometrial hyperplasia, medroxyprogesterone acetate (MPA) is most used.

Various regimens are used: estrogen for 25 days with inclusion of MPA during last 10-13 days of estrogen, 5-6 days with no hormones

-- Combos of estrogens with progestins:

FEM HRT (estradiol plus norethindrone acetate)

ORTH PREFEST (estradiol plus norgestimate)

Route of administration

Vaginal creams (PREMARIN) or a ring device (ESTRING) can be used instead of oral doses . Reduces vaginal dryness, yeast infections and urinary tract infections.

CombiPatch (estradiol/norethindrone acetate) twice weekly transdermal patch Alcohol free, lasts 3.5 days

Progestin Only Contraceptive - Contraception Administration

Oral formulations of norethindrone (Micronor) or levonorgestrel (Ovrette) taken daily

Subdermal implants of etonogestrel (Nexplanon) for slow-release and long-term contraceptive actions (up to four years)

IM injections of medroxyprogesterone (Depo-provera) that provides effective contraception for 3 months

Intrauterine device (IUD) that releases low amounts of progesterone locally (Mirena lasts up to 8 years).

Other Beneficial Effects of

Oral Contraceptives

1. Decreases Dysmenorrhea

2. Decreases benign breast and ovarian cysts

3. Regulates cycle in anovulatory women

4. Decreased blood loss during menstruation

5. Reduction in ovarian and endometrial cancer

Estrogens: ethinyl estradiol

Absorbed efficiently in GI tract. Mestranol is biologically inactive and must be metabolized to ethinyl estradiol. Peak plasma levels within 1 hr after oral administration

Progestins: 19-NOR Steroids

Removal of 19-carbon changed major hormonal effect from an androgen to progestin while maintaining oral activity.

Estranes

have some androgenic activity as well as estrogenic/anti-estrogenic actions. Rapidly absorbed (norethindrone)

Gonanes

More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives (norgestrel, norgestimate, levonorgestrel, drospirenone)

Monophasic

Fixed concentrations of estrogen and progestin, which is taken for 21 days followed by 7 days of "hormone-free" pills.

Biphasic

Fixed concentration of estrogen with 2 different concentration of progestin. Lower concentration in the first 1-14 days and then higher concentration for the next 15 – 21 days. followed by 7 days of “hormone-free” pills.

Triphasic

Fixed concentration of estrogen with 3 different concentrations of progestin. Lower concentration in the first 1-6 days and then higher concentration for the next 7-11 days. Then highest dose 12-21 days followed by 7 days of "hormone-free" pills.

levonorgestrel / ethinyl estradiol - Extended-cycle Birth Control Pill 84/7 formulation

0.15 mg / 0.03 mg

And either placebo or ethinyl estradiol tablets 0.01 mg tablets)

Brand Names: Jolessa, Quasense, Seasonale, Seasonique

Advantages

-- Period once every 3 months

-- Period last about 3 days with decreased bleeding

Side Effects:

-- Breakthrough bleeding and spotting

Emergency Contraceptives

Drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. Emergency contraception prevents pregnancy by delaying or inhibiting ovulation, or release of an egg:

Louisiana HOUSE BILL NO. 1061 - HEALTH/WOMEN'S: Provides for procedures for victims of sexually-oriented criminal offenses. Every state has its own regulations

Emergency hormone contraceptive regimens are highly effective and decrease the risk of pregnancy by 75 percent

To be effective these must be taken within 72 hours of intercourse no more than 120 hours (5 days)

May also inhibit ovulation or fertilization depending on timing of administration Alteration of the endometrium, sperm penetration, and tubal motility are also affected. ESTABLISHED PREGNANCIES ARE NOT HARMED

Two products are available:

Plan B: 0.75 mg levonorgestrel

Preven: 0.25 mg

levonorgestrel and 0.05 mg ethinyl estradiol (this product includes a pregnancy test kit)

Anti-seizure medications

St. John’s wort

Anti-tuberculosis drugs such as rifampin

HIV protease inhibitors

Drugs that disrupt liver metabolism and increase estrogen metabolism in oral contraceptives:

Oral contraceptives effect the activity of other drugs

anticoagulants - increases effectiveness

benzodiazepines - inhibit metabolism in some benzodiazepines

beta-blockers - inhibit metabolism in some benzodiazepines

corticosteroids

tricyclic antidepressants - increase levels in the blood; therefore, higher risk of toxicity and side effects

ABSOLUTE Effects: Contraindications for contraceptives with estrogen

History of thromboembolism, stroke

Impaired liver function

Known or suspected breast cancer

Undiagnosed abnormal vaginal bleeding

Known or suspected pregnancy

Smokers over age 35 (may use progestin-only)

RELATIVE Effects: Contraindications for contraceptives with estrogen

Migraine headaches

Hypertension - ok if <35, or healthy, or BP controlled

Elective surgery: Discontinue 4wks. prior to major surgery

Gallstones/ Cholecystitis

Epilepsy: anti-seizure meds may decrease effectiveness of OCP's

Diabetes: small risk or worsening vascular disease

The Menstrual Cycle | 3D Animation (2/2)

The Menstrual Cycle | 3D Animation (2/2)

Hormonal changes

across the six menstrual cycle subphases. The figure represents changes from a 28 day menstrual cycle. The cycle duration and ovulation timing, however, vary both within and between women.