exam 1

reproductive, bph, oab,ed

Explain the sex hormone axis pathway

hypothalamus releases GnRH which then activates the anterior pituitary gland. The activation of the anterior pituitary releases LH & FSH which then stimulates the gonads to release sex hormones (androgen, estrogen, and progesterone.

What kind of feedback is the sex hormone axis pathway and how so?

It is a negative feedback system and that means when there is a surplus of any of the 3 hormones, it can lead back to the hypothalamus/pituitary and stop GnRH.

Can there be a positive feedback system with the sex hormone pathway?

Yes! It typically happens during a woman's menstrual cycle (days 12-14) where an excess amount of estrogen feeds positively back to the hypothalamus/pituitary.

What are the endogenous agonists, and what receptors do they act on?

-Androgen Receptor--> Dihydrotestosterone (DHT)
-Estrogen Receptor--> Estradiol (E2)
-Progesterone Receptor- Progesterone (P4)

MOA of Endogenous Agonists

A bound steroid becomes free (has to be free in order to have activity). The free steroid then is entered to the target cell by a chaperone protein (Hsp90) and is translocated into the receptor where gene expression occurs for whatever hormone is produced

What is a chaperone protein and which one is involved with the MOA of endogenous agonists?

A chaperone protein helps stabilize and regulate hormone receptors inside the cell. Hsp90 is involved

GnRH Agonists

-leuprolide
-histrelin
-goserelin
-triptorelin
-nafarelin

Indications for GnRH agonists

-Endometriosis
-Uterine fibroids
-Prostate cancer
-Breast cancer
-Precocious puberty

MOA of GnRH

Activate the GnRH receptor (single use stimulates LH and FSH release). But continuous activation of the GnRH receptor results in its eventual desensitization (turns-off LH and FSH release)

Why are GnRH agonists not orally bioavailable?

It is because they are peptide drugs (too big) and have to be injected in order to be metabolized correctly

What are some potential problems associated w/ GnRH agonists?

1. Increase in sex hormones (initial surge) but later on develops worsening symptoms (tumor flare--> cancer)
2. All-or-nothing (either you get all of the drug and it works or it doesn't) (no titration)
3. Long-term suppression (can cause AE such as BMD and hot-flashes which typically occurs in female patients using these agents for endometriosis)

How can you prevent long-term suppression of sex hormones?

Give add-back therapy (sex hormones) along with GnRH agonists
EX)
1. Progestrin-only (norethindrone)
2. Progestrin + Estrogen (norethindrone + ethinyl estradiol)

GnRH Anatagonists

-Cetrorelix
-Ganirelix
-Degarelix
-Relugolix
-Elagolix

Indications for GnRH antagonists

-Fertility therapy (to prevent ovulation)
-Prostate cancer
-Endometriosis

MOA of GnRH antagonists?

competitive inhibition for the GnRH receptor

Delivery forms of GnRH antagonists?

-SC injection (-relix)—>why? peptide structure
-Oral (-golix)

How do GnRH Antagonists differ from GnRH Agonists?

1. No initial surge (So no "tumor flare" when used in cancer)
2. Inhibition is NOT "All-or-nothing" (can be titrated, but this means choosing the right dose is critical for desired effect)

Gonadotrophins

-Menotropins (FSH + LH)
-Urofollitropins (FSH)
-Follitropin (FSH)
-Chorionic gonadotropin (hCG)

Indications for gonadotrophins

-Controlled ovarian stimulation
-Spermatogenesis
-Ovulation induction (hCG)

MOA of gonadotropins

LH, FSH receptor activation (gonadal stimulation)
this means that when the LH and FSH receptors are stimulated it increases the enzymes involved with whichever one and therefore increases the end products

What releases hCG?LH and FSH and what receptors to the act upon?

-Placenta-->hCG and acts upon the LH receptor
-Anterior Pituitary--> LH and FSH and acts upon the LH receptor and FSH receptor respectively

What enzymes are involved with LH and hCG?

P450scc
3b-HSD
17b-HSD

What enzymes are involved with FSH?

-Aromatase
-SHBG (steroid hormone binding globulin)

AE of gonadotropins

• Nausea, cramps
• Breast tenderness
• Ovarian enlargement (abdominal pain)
• Multiple births
• Blood clots (effect of increased E2 levels)
• May promote growth of hormone-sensitive cancers

hCG Abuse

-Abuse in weight loss (people think being on this medication for 3-4 weeks and having 500 cal/day diet will work------> it doesn't)
-Abuse in body building (mfs on steroids end up developing SE such as testicular atrophy and gyno--> they think by taking this med it will reverse these SE---> it doesn't)

Estrogen Receptor Agonists

-Estradiol
-Estradiol cypionate
-Estrogens, conjugated
-Ethinyl estradiol
-Mestranol

Indications for Estrogen Receptor Agonists

•Low E2 (1° ovarian insufficiency)
•Post-menopausal HRT
•Oral contraception
•Feminizing hormone therapy
•Cancer therapy

Sex steroids have low oral bioavailability

True (

What is an example of an estrogen receptor agonist that has an ester group and what does it mean?

Estradiol Cypionate and has an ester group attached to it and that means its an inactive prodrug and is given by IM injection where it is slowly released from site (depot)

What are examples of estrogen receptor agonists that have sulfate groups and what does it mean?

estrone sulfate & equilin sulfate (conjugated estrogens). Having a sulfate group means it is basically an inactive prodrug and requires enzyme activation and sulfates are natural forms found in blood and urine
Fun fact--> these agents are made up of a mix of estrogenic hormones found in horse urine

What are examples of estrogen receptor agonists that have synthetic analogs and what does it mean?

Ehtinyl estradiol and mestranol. Synthetic analogs of estradiol have better pharmacokinetics (absorption, resistance to metabolism, and distribution). Mestranol is a prodrug of ethinyl estradiol, which is active

Progestin Receptor Agonists

-Progesterone
-Levonorgestrel
-Norgestimate

Indications for Progestin Receptor Agonists

•Post-menopausal HRT
•Oral contraception
•Feminizing hormone therapy

What is more commonly used progesterone or synthetic analogs of progesterone?

Synthetic Analogs! Although progesterone can be used as an oral drug, synthetic analogs have better properties

What is an example of a progestin receptor agonist that has a synthetic analog and what does it mean?

Levonorgestrel. Higher potency and selectivity for the progesterone receptor, and better PK properties

What is an example of a progestin receptor agonist that has an ester group and what does it mean?

Norestgimate. Its a prodrug so that means The ester needs to be enzymatically removed for the drug to become active at the PR. This enhances the oral absorption of the drug, which then forms active metabolites.

Androgen Receptor Agonists

-Testosterone
-Testosterone isocaproate
-Methyltestosterone

Indications for Androgen Receptor Agonists

•Low T (laboratory-confirmed)
•Masculinizing hormone therapy
•Cancer therapy

What is an example of an androgen receptor agonist that has an ester group and what does it mean?

Testosterone isocaproate. It is a prodrug given by IM injection (depot) with slow release from the injection site. The lipophilic chains increase fat distribution and protein binding

What is an example of an androgen receptor agonist that has a sulfate group and what does it mean?

Testosterone sulfate. Sulfate of testosterone are natural forms found in blood and urine
Rarely used

What is an example of an androgen receptor agonist that has a synthetic analog and what does it mean?

Methyltestosterone. Methyl group at 17 position improves resistance to metabolism and have better PK.

Anti-estrogens

Fulvestrant

Indication for anti-estrogens

breast cancer

Fulvestrant Info

-An ER antagonist (Blocks ER from binding to DNA and increases receptor degradation)
-AKA "Selective Estrogen Receptor Degrader" (SERD)

Anti-progestin

Mifepristone

Indication for anti-progestrin

Pregnancy termination

Mifepristone can be used with...

used with misoprostol

Anti-androgens

-Spironolactone**
-Apalutamide
-Bicalutamide**
-Darolutamide
-Enzalutamide
-Flutamide
-Nilutamide
** need to know

Indication for anti-androgens

•Prostate cancer (-lutamide)
•Acne vulgaris (spironolactone)
•PCOS (spironolactone)

Spironolactone Info

-Both an AR and MR antagonist
-Used for BP
-Used for androgen effects (for PCOS, acne, and feminizing hormone therapy)

Bicalutamide Info

-Non-steroid anti-androgen
-Competitive and highly selective for the androgen receptor
-Mainly indicated for prostate cancer

SERMs (selective estrogen receptor modulators)

-Clomiphene
-Ospemifene
-Bazedoxifene
-Raloxifene
-Tamoxifen
-Toremifene

Indication for SERMs

•Fertility therapy (clomiphene)
•Vaginal dryness (ospemifene)
•Osteoporosis (bazedoxifene, raloxifene)
•Breast cancer (tamoxifen, toremifene)

SPRMs (selective progesterone receptor modulators)

Uripristal acetate

Indication for SPRMs

•Emergency contraception
•Uterine fibroids (leiomyomas)

MOA of SERMs and SPRMs and delivery forms

-Selective receptor activation OR inhibition in different tissues (tissue dependent)
-Both agents are orally available

What are the side effects associated with SERM?

-Anti-Estrogenic effects (hot flashes, muscle cramps, vaginal dryness) (acts on breast and hypothalamus)
-Estrogenic effects (blood clot risk, endometrial proliferation, bleeding, uterine cancer) (acts on endometrium, vasculature, and bone tissue)

Which drug is most commonly used to treat breast cancer and why?

Tamoxifen and this is due to the androgenic effects it has on the breast tissue. Since it is a prodrug, it requires metabolic activation.

CYP17A1 Inhibitors

Abiraterone

What hormones decreases when CYP17A1 is inhibited?

-Cortisol
-Androgens
-Estrogens

Indication for CYP17A1 Inhibitors

Prostate cancer

Abiraterone MOA

-Analog of pregnenlone
-Used to block androgen synthesis in advanced prostate cancer
-Inhibits cortisol and estradiol synthesis
-Aldosterone biosynthesis is increased which causes metabolic SE.
**Drug basically targets enzymes that converts endogenous compounds into testosterone (so androgen won't promote prostate growth)

5-alpha reductase (5-AR) inhibitors

Dutasteride and Finasteride

Indication 5-AR inhibitors

-Prostate Cancer
-BPH
-Male Pattern Baldness
-Female Hirsutism (occasionally)

What hormones decreases when 5-AR is inhibited?

DHT

5-AR inhibitors MOA

Inhibits 5-alpha reductase which therefore decreasing DHT levels

5-AR info

This enzyme helps develop DHT and is made in androgen receptor sensitive tissues.

Aromatase inhibitors

-Anastrozole
-Letrozole
-Exemestane

What hormones decreases when aromatase is inhibited?

estrogen

Indication for aromatase inhibitors

•Breast + other cancers
•Ovulation induction in women with PCOS (letrozole)

Aromatase inhibitor MOA

Aromatase converts testosterone into estradiol. By inhibiting aromatase level of estradiol decreases
-Anastrozole and Letrozole are competitive
-Exememstane is irrversible.

Hytrin generic

Terazosin

Cardura generic

Doxazosin

Minipress generic

Prazosin

UroXatral generic

Alfuzosin

Flomax generic

Tamsulosin

Rapaflo generic

Silodosin

Proscar generic

Finasteride

Avodart generic

Dutasteride

Cialis generic

Tadalafil

What are the alpha blockers?

doxazosin, prazosin, terazosin, tamsulosin, silodosin, alfuzosin

What are the 5-alpha reductase inhibitors?

Finasteride, Dutasteride

Which alpha blockers are non-uroselective?

Non-uroselective?--->doxazosin, prazosin, terazosin

Which alpha blockers are Uroselective?

tamsulosin, silodosin, alfuzosin

What is 1st line for the treatment of BPH?

1st line-->Alpha-blockers and tamsulosin (modestly effective & can work within just a few days)

What is 2nd line for the treatment of BPH?

2nd line-->5-alpha-reductase inhibitors (added as adjunctive therapy if sx of BPH doesn't improve 4-12 weeks)

What is 3rd line for the treatment of BPH?

3rd line---> Tadalfil (Only PDE5i shown for BPH and good to use if patient has ED)

Tadalfil Info for BPH

-DO NOT USE w/alpha blocker---> hypotension risk
-Can be used w/5-ARi---> Entadfi (Finasteride 5mg/ Tadalafil 5mg daily for 26 weeks) (CrCl

Is there an OTC that can be used for BPH?

Yes! Saw Palmetto. Okay to try but no real evidence on efficacy (used in europe)
Dosing: 160 mg BID
AE: GI effects

Obstructive Findings

Stream weakness
Hesitancy
Inability to stop abruptly
Post-void dribbling
Sensation of bladder fullness
Urinary retention

Irritative Findings

Frequency
Urgency
Nocturia
Pain on urination
Urge incontinence

AUA symptom index

Score: 0-7= Mild
8-19 = Moderate
20-35 = Severe

Aggravating Meds

Diuretics (increased urine frequency)
Sympathomimetics--->Decongestants, sudafed (alpha-agonists can cause constriction in the nose and prostate)
Anticholinergics---> Antihistamines, Antidepressants, Antipsychotics, GI antispasmodics (can cause urinary retention)

Tests for BPH

PSA (prostate specific antigen)
DRE (digital rectal exam)

Alpha-adrenergic blockers

Rapid symptom relief
Full benefit in 2-3 months
4-6 point improvement
ADEs: orthostasis, nasal congestion, asthenia, dizziness
Interacts with PDE5 inhibitors (hypotension)

alpha blockers some adverse effects

-1st dose effect (hypotension: orthostatic)
-interacts w/ PDE5i
-prazosin (avoid use due to CNS SE; used for pts w/ PTSD)
-Floppy Iris Syndrome (Surgery 1st then initiate drug)
-Silodosin (Highest incidence of abnormal ejaculation among alpha blockers)
-AE: dizziness, lack of energy, decreased libido, insomnia, rhinos, and abnormal ejaculation

alpha blockers timing when to give

-non-uroselective (usually given at HS)
-uroselective (given either before or after meal)

CYP pathway uroselective alpha blockers

-Alfuzosin (Interacts with CYP 3A4; CI w/ potent CYP3A4i; Hypotension with sidenafil)
-Tamsulosin (Interacts w/ CYP3A4 & 2D6)

finasteride (5-ARi) facts

-Effective in prostates >40 mL, reduces need for surgery, reduces urinary retention, reduction in prostate volume;
-Pregnancy category X;
-PSA levels cut in half;

finasteride onset

6 months