Androgens/Antiandrogens

Androgens

• _______ —> primary secreted androgen in men (______ ______) and women ( ______ ______ and ______ ______ )

• ______ and ______ (DHEA) —> weak androgens —> can be converted to ______

• testosterone, Leydig cells, corpus luteum, adrenal cortex

• androstenedione, dehydroepiandrosterone, testosterone

Androgen Synthesis and Secretion

1. hypothalamus —> ______ from its pulse generator

2. GnRH acts on the ______ ______ to stimulate the release of gonadotropins —> ______ and ______

3. pulsating GnRH secretion causes an ______ in LH and FSH, while continuous GnRH secretion causes ______ in LH and FSH

4. during the 1st trimester, the ______ produces ______ —> which mimics LH activity

5. stimulation of Leydig cells results in increased ______

6. Leydig cells produce about ______% of male testosterone, while the adrenal cortex contributes about ______%

7. in females, approximately ______% of testosterone comes from the adrenal cortex via DHEA

• GnRH

• anterior pituitary, FSH, LH

• increase, decrease

• placenta, hCG

• de novo testosterone biosynthesis

• 95, 5

• 50

Male Serum Testosterone Concentration

• during gestation, testosterone production is stimulated by ______

• during infancy, testosterone levels briefly rise due to ______ stimulation

• testosterone levels remain low during childhood because the ______ axis is inactive

• at puberty, testosterone production sharply increases in response to elevated ______ levels

• in adulthood, testosterone levels remain high but gradually ______ with age

• daily testosterone secretion is ______ and ______ —> occurring about every ______ hours

• testosterone levels are highest at ______ and ______

• hCG

• LH

• hypothalamic-pituitary

• LH

• decline

• diurnal, pulsatile, 2

• 8 AM, 8 PM

Testosterone Binding 

• free testosterone (____%) —> active form that diffuses into tissues

• albumin-bound (~____%) —> weakly bound, still bioavailable

• SHBG-bound (~______%) —> strongly bound, biologically inactive

• 2

• 60

• 40

Metabolism of Testosterone —> active and inactive metabolites

• Testosterone is converted to dihydrotestosterone (DHT) by the enzyme ________.

  • Dihydrotestosterone (DHT) is about ________ as abundant as testosterone but is a more potent androgen.

• Testosterone is converted to estradiol (E₂) by the enzyme ________.

  • A ring into a phenol group.

• The two active metabolites of testosterone are ________ and ________.

• 5a-reductase

• 1/10

• aromatase (CYP19)

• dihydrotestosterone (DHT), estradiol

Direct and Indirect Effects of Testosterone

• DHT binds to ______ receptors to exert its effects on external genitalia and hair follicles.

  • External genitalia → differentiation during ________ and maturation during ________.

  • Hair follicles → increased growth during ________.

  • Adult → contributes to ________ diseases.

• Testosterone directly binds to ______ receptors in internal genitalia, skeletal muscle, erythropoiesis, and bone.

  • Internal genitalia → ________ development during gestation.

  • Skeletal muscle → increases ________ and ________ during puberty.

  • Stimulates ________ and supports ________ maintenance.

• Estradiol binds to ________ receptors, mainly affecting bone and libido.

  • Bone → ________ closure and increased ________.

  • Contributes to ________.

• androgen

• gestation, puberty

• puberty

• prostatic

• androgen

• wolffian

• mass, strength

• erythropoiesis, bone

• estrogen

• epiphyseal, density

• libido

Dihydrotestosterone

• the affinity of DHT for the androgen receptor is ______ than that of testosterone

• the conversion of testosterone to DHT involves the reduction of the ______ double bond

• greater

• 4,5-

Effects via the androgen receptor —> In Utero

• formation of male ______ —> testosterone and external ______ —> dihydrotestosterone

internal, genitalia

In Utero Deficiency

• caused by ______ or ______ receptors

• results:

  • first trimester —> degree of deficiency determines the degree of ______ characteristics

  • third trimester —> results in ______ genital development

• the role of androgens during infancy is ______

• CYP17, dysfunctional

• female

• incomplete

• unknown

Effects via the androgen receptor —> Puberty

• promote ______ capability

• cause drastic effects of a variety of ______ simultaneously

• increased ______ production —> acne

• increase ______ growth

• increase ______ mass and ______

• promote ______ growth

• stimulate ______ —> inc. Hgb and Hct

• ______ changes like aggressiveness

• reproductive

• tissue

• sebum

• hair

• muscle, strength

• bone

• erythropoiesis

• behavior

Deficiency in Puberty

• ______ (increase/decrease) traits —> on previous flashcard

• ______ —> breast tissue enlargement due to relative estrogen excess

• decreased

• gynecomastia

Effects via the androgen receptor —> Adulthood

• maintains adult ______ characteristics

• contributes to ______ ______ ______

• linked to ______ issues

  • benign prostatic hyperplasia —> ______ in prostatic cells converts testosterone to DHT

  • prostate cancer —> testosterone is not the cause, but the cancer ______ on testosterone

• male

• male pattern baldness

• prostate

• 5a-reductase Ⅱ

• depends

Adulthood Deficiency

• regression of testosterone effects depends on the ______ and ______ of deficiency

• if testosterone deficiency is substantial, ______ symptoms occur first

• rapid —> decreased ______ and ______

• gradual —> decreased ______ mass, ______, ______ and ______ ______ density

• degree, duration

• rapid

• libido, energy

• muscle, Hgb, Hct, bone mineral

Effects via the androgen receptor —> Senescene

• testosterone ______ and SHGB ______ gradually with age

• results in decreased —> (4)

• decrease, increase

• energy, libido, muscle mass and strength, bone mineral density

Effects via the estrogen receptor

• conversion of testosterone to estradiol results in _____% of estrogen in males —> rest directly from ______

• promotes fusing of ______

• may play a role in regulating ______

• a deficiency of estradiol during ______ prevents ______ closure —> individuals develop ______ limbs compared to the ______

• 85, testes

• epiphysis

• libido

• puberty, epiphyseal, long, trunk

Testosterone — PK Issues

• testosterone is ______ absorbed orally but rapidly ______ by the liver

• because testosterone undergoes extensive ______ metabolism, most formulation are designed to bypass this effect

• to avoid first-pass metabolism, testosterone preparations are given through alternative routes such as ______, ______ patch, and ______ ______

• readily, metabolized

• first-pass (hepatic)

• IM, transdermal, topical gel

Testosterone Esters

• are formed by adding a substituent to the ______ group on the testosterone molecule

• examples of testosterone esters —> (2)

• act as ______ that are converted to active testosterone through ______ ______ in vivo

• compared to testosterone, these esters are more ______ and are usually dissolved in ______ for IM injection every ______ weeks

• after injection, testosterone levels are initially ______ than normal but drop to ______ levels before the next dose

• 17a-OH

• testosterone enanthate, testosterone cypionate

• prodrugs, ester hydrolysis

• lipophilic, oil, 2-4

• higher, low-normal

Testosterone Toxicity —> Endogenous Doses

• has no true “______ ______” but ______ effects such as acne and aggression may occur

• mainly seen in the presence of ______ illnesses

  • increase ______ in someone with erythrocytosis

  • increase ______ and ______ retention effects in CHF

• side effects, puberty-like

• concomitant

• erythropoiesis

• sodium, water

Testosterone Toxicity —> High Dose

• decrease ______ size and function due to ______ feedback

• ______ can occur from testosterone’s aromatization to estradiol

• can cause ______ and ______ and ______ retention

• in women, and children, high testosterone levels produce ______ male testosterone effects

• testicular, negative

• gynecomastia

• erythrocytosis, sodium, water

Testosterone Toxicity —> Cardiovascular System

• According to the FDA, there is a possibility of increased ________ risk associated with testosterone use, despite ________ and inconclusive evidence.

• some evidence suggests a higher cardiovascular risk in ______ men

• risk is slightly higher in patients with existing ______ ______ disease

• the greatest risk occurs with ______ preparations that lead to ______ concentrations of testosterone

• cardiovascular risk is unlikely in men who are legitimately ______ and require replacement therapy

• cardiovascular, conflicting

• older

• coronary artery

• injectable, supraphysiological

• hypogonadal

Testosterone Undecanoate

• orally ______, long-acting ______ ester

• when given orally (in oil), it bypasses the ______ ______ pass effect by being absorbed through the ______ system

• when administered IM (in oil), it provides stable testosterone concentrations for about ______ months

• bioavailable, testosterone

• hepatic first, lymphatic

• 2

Testosterone Undecanoate —> Injection

• more ______ than other esters

• not used in age-related ______ or patients under ______ years old

• rare but severe risks can occur soon after injection, including:

  • pulmonary oil ______ and ______

  • due to these risks, testosterone undecanoate has highly ______ availability and requires ______ after administration

• toxic

• hypogonadism, 18

• microembolism, anaphylaxis

• restricted, monitoring

Alkylated Androgens

• modified forms of testosterone with a substituent at the ______ position

• orally ______, but are less ______ than testosterone

• additional toxicity can occur even at ______ doses

• _______ —> may cause ______ by blocking bile flow, and occasionally ______ _____

• can cause a decrease in ______ due to increased metabolism via hepatic triglyceride lipase

• examples —> (5)

• 17 a

• bioavailable, androgenic

• physiological

• hepatotoxicity, cholestasis, peliosis hepatis

• HDL

• methyltestosterone, oxandrolone, stanozolol, fluoxymesterone, danazol

Male Senescene

• testosterone therapy in older men has shown evidence for an increase in ______ and ______ and a decrease in ______

• decrease ______, ______ ______, and ______

• testosterone therapy may worsen ______ or increase the incidence of ______ cancer

• bone mineral density, muscle mass, fat mass

• mortality, myocardial infarction (MI), stroke

• BPH, prostate

Hypogonadism

• ______ indication for testosterone therapy

• monitor for efficacy

  • ______ ______

  • ______ ______ —> normal puberty effects in boys or restoration of male characteristics in adults

• primary

• serum concentrations

• hormone effects

Other Indications

• can be used in catabolic and ______ states

  • generally only effective for this indication in muscle wasting associated with ______

• used in ______ transition

  • goal plasma levels —> ______ mg/day

• wasting

• AIDS

• female-to-male

• 300-500

Athletic Performance Enhancement

• testosterone use for athletic performance is ______ by the FDA because it is not a legitimate indication and has many adverse effects

• “anabolic steroids" refer to ______-alkylated agents which are easily detectable and toxic

• ______ esters or ______ are less detectable

• androstenedione (does / does not) work

• name two other androgens sometimes used for performance enhancement:

• not recommended

• 17a

• testosterone, hCG

• does not

• DHEA, tetrahydrogestrinone (novel structure)

Inhibitors of Testosterone Secretion

• GnRH antagonist inhibit ______, and therefore inhibit ______ secretion

• Ketoconazole inhibits ______ enzymes decreasing both ______ and ______ —> although it’s mainly used to reduce ______ levels

• LH, testosterone

• CYP, cortisol, testosterone, cortisol

Inhibitors of Androgen Action

• Androgen Receptor Antagonists

  • ______/______/______/______ —> indicated for metastatic prostate cancer

    • often used in combination with a ______ analogue

      • androgen receptor blocker inhibits adrenal testosterone action

      • GnRH analogue suppresses testosterone release from Leydig cells in the testes

  • ______ weakly inhibits androgen receptors as a side effect of its intended ______

  • common side effect —> ______

• 5a-reductase inhibitors

  • ______/______ —> block conversion of testosterone to dihydrotestosterone

    • indicated for ______ and ______ ______ ______

    • adverse effects include ______ and ______

• flutamide, bicalutamide, nilutamide, enzalutamide

• GnRH

• spironolactone, aldosterone

• gynecomastia

• finasteride, dutasteride

• BPH, male pattern baldness

• impotence, gynecomastia