HIP 308

METABOLIC & ENDOCRINE

DRUGS

Dr. Gitau Chege

Gitau sc Notes
 Androgens, Antiandrogens,
Anabolic Steroids & Male
contraception
Dr. Gitau SC

Gitau SC
 Steroidogenesis
• Main steroidogenic components of the testis are the interstitial cells
of Leydig
• Testosterone synthesis begins with acetate ( either from glucose or
products of lipid metabolism) which is converted to cholesterol
• Pregnenolone is formed by side chain cleavage in the inner
mitochondria membrane
– A rate limiting reaction stimulated by LH
– Pregnenolone returned to the cytoplasm for synthesis
• Testosterone synthesis then occur via 2 pathways

Gitau SC
 Regulation of Plasma Testosterone
Hormonal interrelationships
between the hypothalamus,
anterior pituitary, & testes.
Solid arrows, Excitatory effects; dashed
arrows, inhibitory effects.
GnRH, gonadotropin-releasing hormone;
FSH, follicle-stimulating hormone;
LH, luteinizing hormone.
(Modified with permission from Fox SI.
Human Physiology (3rd ed.). Copyright 1990
Wm. C. Brown, Dubuque, IA.

Gitau SC
 Schematic representation of the serum testosterone
concentration in males from early gestation to old age

• Testosterone is synthesized by Leydig cells of the testes at the rate

of about 8 mg/24 hrs, providing a plasma concentration of 0.5 - 0.6
µg/dL.
• In women, testosterone primarily serves as a precursor to estrogens
but also is the predominant circulating androgen.
Gitau SC
 Sex Hormone–Binding Proteins
• Circulating testosterone is reversibly bound to two major plasma
proteins,
– Albumin – (non specific)
– Gamma globulin (sex hormone–binding globulin (SHBG):
(highly specific)
• Under physiological conditions, only 2% is free; 40% bound to
albumin & 58% to SHBG

Gitau SC
 Sex Hormone–Binding Proteins
• Increased SHBG levels due to
– High estrogen or oral contraceptives
– Liver cirrhosis
– During normal aging in male
– Hyperthyroidism
– Hypogonadism
• Decreased SHBG levels due to
• Androgen replacement
• Chronic glucocorticoid therapy
Gitau SC
 Pharmacological
Effects

Direct effects of testosterone and indirect

effects mediated by dihydrotestosterone or
estradiol.
Gitau SC
 Preparations available & Relative
Androgenic: Anabolic Activity in Animals
Androgenic : Anabolic
Drug Activity
Testosterone Esters: Esterifying a 1:1
fatty acid to the 17 α hydroxyl more lipophilic than
group: testosterone
• Testosterone Cypionate, or
enanthate, heptanoate
• Methyltestosterone 1:1
• Fluoxymesterone 1:2
• Oxymetholone 1:3
• Oxandrolone 1 : 3 to 1 : 13
• Gitau
Nandrolone
SC
decanoate 1 : 2.5 to 1 : 4
 Pharmacokinetics
 Testosterone is rapidly absorbed orally,
 However, it is largely converted to inactive metabolites, &
only ≈ ⅙ the dose is available in active form.
 Parenteral testosterone has a more prolonged absorption time &
greater activity in the propionate, enanthate, undecanoate, or
cypionate ester forms.
 These derivatives are hydrolyzed to release free testosterone at
the site of injection.

Gitau SC
 Pharmacokinetics
 Alkylated Androgens

 17α-alkylated androgens were called anabolic steroids

 Testosterone derivatives alkylated at the 17 position, e.g.,

methyltestosterone & fluoxymesterone, are active when given

by mouth

 Biological assays are still used in the investigation of new

compounds, i.e.,

 measured by trophic effects on muscles

Gitau SC
 Pharmacodynamics

 Acts thro’ intracellular androgen receptor in target cells (skin,

prostate, seminal vesicles & epididymis)

 Result in growth, differentiation, & synthesis of a variety of

enzymes & other functional proteins.

 Also converted to 5-dihydrotestosterone by 5α-reductase.

(Dihydrotestosterone is the dominant androgen)

Gitau SC
 Clinical Use
1. Replacement therapy in hypogonadal Men.

 Needed (rather than gonadotropin) when spermatogenesis is

desired

 Transdermal patches, gels, or IM depot

 NB: In patients with hypopituitarism, androgen is added after

puberty

 long-acting agents such as testosterone enanthate or

cypionate in doses of 50 mg IM, initially q4h, then q3h, &
finally every 2 weeks, with each change taking place at 3-
Gitau SC month intervals
 Clinical Use
2. Protein Anabolic Agents (In conjunction with diet & exercises)

 Reverse protein loss after trauma, surgery, or prolonged

immobilization & in patients with debilitating diseases.

3. Aneamia :

 Large doses were employed in the RX of refractory anemias;

 Aplastic anemia, Fanconi's anemia, sickle cell anemia,

myelofibrosis, & hemolytic anemias.

 NB:

 Recombinant erythropoietin has largely replaced androgens for

Gitau SC
this purpose
 Clinical Use
4. Osteoporosis :

 Used either alone or in conjunction with estrogens.

 NB:

 With the exception of substitution therapy in hypogonadism,

bisphosphonates have replaced androgen

5. Aging-

 Under investigation

 Preliminary studies showed increase in lean body mass,

hematocrit & a decrease in bone turnover
Gitau SC
 ADRs
 NB:

 Largely due to their masculinizing actions & are most

noticeable in women & pre-pubertal children

 ˃ 200 – 300 mg of testosterone per month in women:

 Hirsutism, acne, amenorrhea, clitoral enlargement, & deepening

of the voice

 Endometrial bleeding upon discontinuation ( for some with

progestogen activity)

Gitau SC
 ADRs
 17 α-alkylated androgens:

 Hepatic including cholestasis

 Uncommonly peliosis hepatis (blood-filled hepatic cysts)

 Replacement therapy in men may cause

 Acne

 Sleep apnea

 Erythrocytosis

 Gynecomastia

 Azoospermia.
Gitau SC
 C/I & Cautions

 Pregnancy (or women who may become pregnant during therapy.

 Carcinoma of the prostate or breast

 Infants & young children

 Creatinuria (methyl testosteone)

Gitau SC
 Antiandrogens

Gitau SC
 Classification of antiandrogens

i. Androgen Receptor Antagonists

 (Flutamide, Bicalutamide, & Nilutamide, cyproterone,

abiraterone, spirinolactone

ii. 5 α-Reductase Inhibitors

 (Finasteride (PROSCAR), Dutasteride(AVODART)

iii. Inhibitors of Androgen Biosynthesis: ketoconazole

Gitau SC
 Pharmacodynamics
i. Androgen receptor antagonist :
Cyproterone & Cyproterone acatate

 Inhibit the action of androgens at the target organ.

 Acetate form has a marked progestational effect that

suppresses the feedback enhancement of LH & FSH, leading
to a more effective antiandrogen effect

Flutamide : Non steroidal competitive antagonist at the androgen

receptor

Bicalutamide & Nilutamide : Potent orally active antiandrogens

Gitau SC
 Pharmacodynamics
i. Androgen receptor antagonist (cont):
 Spironolactone

 Competitive inhibitor of aldosterone ,

 Competes with dihydrotestosterone for the androgen

receptors in target tissues.

 Reduces 17-hydroxylase activity, lowering plasma levels

of testosterone & androstenedione.

Gitau SC
 Pharmacodynamics
ii. 5α-Reductase inhibitors: e.g., Finasteride & Dutasteride
 Result in reduction in dihydrotestosterone
iii. 17-hydroxylase inhibitor e.g., Abiraterone.
 Inhibit hydroxylation of progesterone or pregnenolone thus
preventing androgens formation
iv. Steroid Synthesis Inhibitors: ketoconazole, spirinolactone
 Covered under adrenal pharmacology

Gitau SC
 Pharmacokinetics

• Finasteride
– t½ 8 hrs (longer in elderly )
– 40-50% metabolized.
• Both Finasteride & Dutasteride orally active

Gitau SC
 Indication
i. Benign prostatic hyperplasia-(Finasteride (5 mg/d) &
Dutasteride).
 Dutasteride use in advanced prostatic carcinoma is under
study
ii. Rx of
a) Hirsutism in women
b) Early male pattern baldness in men
 Finasteride, Cyproterone & cyproterone acetate : (Dose
1 mg/d)

Gitau SC
 Indication
 Flutamide

i. Prostatic carcinoma.

 Result in some improvement in most pts with prostatic

carcinoma who have not had prior endocrine therapy.

ii. Management of excess androgen effect in women

 Bicalutamide & Nilutamide ;

 Metastatic carcinoma of the prostate.

 Used in combination with a GnRH analog (to reduce tumor

flare)
Gitau SC
 Indication
 Spironolactone

i. Rx of hirsutism in women at a dosages of 50–200 mg/day

As effective as finasteride, flutamide, or cyproterone in this

condition

ii. HF & hepatorenal syndrome)

Gitau SC
 Chemical Contraception in Men
 No effective oral contraceptive
 various androgens, e.g. testosterone & testosterone enanthate
(400 mg per month) produced azoospermia in ˂ ½ the men Rx
i. Preliminary studies indicate that the IM admin of 100 mg of
testosterone enanthate weekly together with 500 mg of
levonorgestrel daily orally can produce azoospermia in 94% of
men.
ii. GnRH antagonist in combination with testosterone has been
shown to produce reversible azoospermia in nonhuman primates.

Gitau SC
 Chemical Contraception in Men
 Gossypol, cottonseed derivative, destroys elements of the
seminiferous epithelium but does not significantly alter the
endocrine function of the testis.
 99% of men Rx with 20 mg/d of gossypol or gossypol acetic acid
for 2 months, followed by a maintenance dosage of 60 mg/wk
developed sperm counts below 4 million/mL
 ADE; Hypokalemia (transient paralysis)
 Has been abandoned as a male contraceptive candidate.

Gitau SC