Male Reproductive System Drugs – Androgens

Androgens are male sex hormones, which include testosterone (produced in the testes) and androgens (produced in the adrenal glands).

Testosterone (Duratest, Testoderm) is the primary natural androgen and is the classic androgen used today. It is used for treatment of certain breast cancers and hypogonadism, a condition where there is undeveloped testis. All testosterones are class III-controlled substances.

Therapeutic Action

The desired and beneficial actions of androgens are as follows:

• Growth and development of male sex organs and the maintenance of secondary male sex characteristics.
• Increase the retention of nitrogen, sodium, potassium, and phosphorus and decrease the urinary excretion of calcium.
• Increase protein anabolism and decrease protein catabolism.
• Increase the production of red blood cells.

Indications

Androgens are indicated for the following medical conditions:

•Danazol is used for treatment of endometriosis, fibrocystic breast disease, and hereditary angioedema. It does this by inhibiting the hypothalamic-pituitary-adrenal (HPA) and gonadotropin-releasing hormones (GnRH), leading to a drop in follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Pharmacokinetics

Here are the characteristic interactions of androgens and the body in terms of absorption, distribution, metabolism, and excretion:

Contraindications and Cautions

The following are contraindications and cautions for the use of androgens:

• Allergy to androgens or other ingredients in the drug. Prevent hypersensitivity reactions.
• Pregnancy, lactation. Potential adverse effects on the neonate. It is not clear whether androgens enter breast milk.
• Presence of prostate or breast cancer in men. Aggravated by the testosterone effects of the drug.
• Liver dysfunction, CV disease. Can be exacerbated by the effects of the hormones.
• Topical forms of testosterone have a Black Box Warning alerting user to the risk of virilization in children who come in contact with the drug from touching the clothes and skin of the man using the drug.
• Danazol has Black Box warning regarding the risk of thromboembolic events, fetal abnormalities, hepatitis, and intracranial hypertension.

Adverse Effects

Use of androgens may result to these adverse effects:

• Androgenic effects: acne, edema, hirsutism (increased hair distribution), deepening of the voice, oily skin and hair, weight gain, decrease in breast size, and testicular atrophy.
• Antiestrogen effects: flushing, sweating, vaginitis, nervousness, and emotional lability.
• Common effects: headache (possibly related to fluid and electrolyte changes), dizziness, sleep disorders and fatigue, rash, and altered serum electrolytes.
• A potentially life-threatening effect that has been documented is hepatocellular cancer

Interactions

• The following are drug-laboratory interactions involved in the use of androgens:
• •Decreased thyroid function
• •Increased creatinine and creatinine clearance (results that are not associated with disease states)
• •These effects can last up to 2 weeks after therapy has been discontinued.’

Name of the Androgen Drugs

1. Danazol
2. Fluoxymesterone
3. Testosterone
4. Methyltestosterone

1.Danazol

Mechanism Of Action:

Suppresses pituitary-ovarian axis by inhibition of pituitary gonadotropin output

Indications:

• Endometriosis
• Fibrocystic Breast Disease
• Hereditary Angioedema

Contraindications & Cautions:

• Pregnancy, breastfeeding
• Porphyria
• Undiagnosed abnormal genital bleeding
• Severe liver/renal/cardiac disease
• Androgen-dependent tumor
• Active thrombosis or thromboembolic disease and history of such events
• Hypersensitivity

Because Danazol may cause some degree of fluid retention, conditions that might be influenced by this factor, such as epilepsy, migraine, or cardiac or renal dysfunction, polycythemia and hypertension require careful observation. Use with caution in patients with diabetes mellitus.

Metabolism and Half- Life:

• Half-Life: 4.5 hr
• Peak Plasma Time: 2 hr
• Bioavailability: well absorbed
• Metabolism: extensively in the liver to 2-hydroxymethyl ethisterone
• Metabolites: 2-hydroxymethyl ethisterone (activity unknown)
• Excretion: mainly in urine, small amount in feces

Drug interactions:

• Prolongation of prothrombin time occurs in patients stabilized on warfarin
• Therapy may cause an increase in carbamazepine levels in patients taking both drugs
• This drug can cause insulin resistance; use caution when using with antidiabetic drugs
• This drug may raise plasma levels of cyclosporin and tacrolimus, leading to an increase of renal toxicity of these drugs; monitoring of systemic concentrations of these drugs and appropriate dose adjustments may be needed when used concomitantly with danazol
• Danazol can increase the calcemic response to synthetic vitamin D analogues in primary hyperparathyroidism; the risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with statins such as simvastatin, atorvastatin, and lovastatin; caution should be exercised if used concomitantly

Side- Effects:

• Intracranial hypertension
• Increased blood pressure
• Thromboembolism
• Anxiety
• Depression
• Dizziness
• Urticaria

Androgenic Effects (common)

• Mild hirsutism
• Decreased breast size
• Voice changes
• Sore throat, acne
• Increased oiliness of skin or hair
• Hair loss

Nursing Considerations

• Use of danazol in pregnancy is contraindicated. A sensitive test (e.G., Beta subunit test if available) capable of determining early pregnancy is recommended immediately prior to start of therapy.
• A non-hormonal method of contraception should be used during therapy
• If a patient becomes pregnant while taking danazol, administration of the drug should be discontinued and the patient should be apprised of the potential risk to the fetus. Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.
• Patients should be watched closely for signs of androgenic effects some of which may not be reversible even when drug administration is stopped.
• Periodic liver function tests and ultrasonography should be performed.
• Monitor CPK, glucose tolerance, glucagon, thyroid binding globulin, sex hormone binding globulin, other plasma proteins, lipids and lipoproteins.
• Monitor blood glucose levels and vital signs regularly.

Patient/ Family Education:

• Importance of advising patients of the potential for serious adverse effects associated with misuse and abuse of androgens.
• Risk of virilization in females. Advise female patients to contact their clinician if they notice hoarseness, acne, or the growth of facial hair.
• Importance of informing clinicians of headache, nausea and vomiting, or visual disturbances.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.
• Importance of women using nonhormonal contraceptive measures.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.
• Inform the female client regarding the chances of alterations in menstruation.

2. Fluoxymesterone

Mechanism of Action:

Synthetic derivative of testosterone with predominantly androgenic activity; promoting growth and development of male sex organs and maintaining secondary sex characteristics in androgen-deficient males

Indications:

In the Male

• Replacement therapy in conditions associated with symptoms of deficiency or absence of endogenous testosterone.
• Primary hypogonadism (congenital or acquired)— testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy.
• Hypogonadotropic hypogonadism (congenital or acquired)—idiopathic gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.
• Delayed puberty, provided it has been definitely established as such, and is not just a familial trait

In the Female

palliation of androgen-responsive recurrent mammary cancer in women who are more than one year but less than five years postmenopausal, or who have been proven to have a hormone-dependent tumor as shown by previous beneficial response to castration.

Contraindications and Cautions :

• Known hypersensitivity to the drug
• Males with carcinoma of the breast
• Males with known or suspected carcinoma of the prostate gland
• Women known or suspected to be pregnant
• Patients with serious cardiac, hepatic or renal disease

Cautions

Benign prostatic hypertrophy, males with delayed puberty, geriatric pts, pediatric pts

Hypercalcemia may occur in breast CA or immobilized pts

Metabolism and half- life:

• Half-Life: 9.2 hr, longer t1/2 than natural androgens
• Bioavailability: PO: rapidly absorbed
• Protein Bound: 98%
• Metabolism: liver
• Excretion: urine (90%)

Drug Interactions:

• Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypo-prothrombinemia.
• Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.
• In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

Side – Effects:

• Edema
• Acne
• Breast soreness
• Priapism
• Menstrual irregularities
• Virilization
• Gynecomastia
• Suppression of clotting factors II, V, VII
• Anaphylaxis

 Nursing Considerations

• This medicine may affect blood sugar levels. Monitor blood sugar levels regularly
• This drug is banned from use by athletes in athletic organizations.
• Watch for serious side- effects in both males and females.
• This drug must not be used during pregnancy. It may harm a fetus.
• Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia.
• Hypercalcemia may occur in immobilized patients and in patients with breast cancer. If this occurs, the drug should be discontinued.
• Women should be observed for signs of virilization which is usual following androgen use at high doses.
• Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy.
• liver function tests and serum cholesterol levels should be obtained periodically.
• Periodic (every six months) X-ray examinations of bone age should be made during treatment of prepubertal males to determine the rate of bone maturation and the effects of androgen therapy on the epiphyseal centers.
• Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-term androgen administration.
• Pediatric Patients: Skeletal maturation must be monitored every six months by an X-ray of the hand and wrist

Patient/ Family Teaching:

• Men should be informed that , if they experience side effects including difficulty urinating, frequent or prolonged erections, or breast swelling/tenderness should inform doctor.
• Women should tell their doctor if they experience side effects including deepening voice, unusual hair growth, or irregular menstrual periods.
• It is recommended that women using this medication use 2 forms of birth control (such as condoms and birth control pills) while taking this medication.
• Inform the patient that Sexual problems and reproduction concerns may happen.
• Inform females that menstrual irregularities may occur. Women may go through signs of menopause (change of life) like vaginal dryness or itching. Vaginal lubricants can be used to lessen vaginal dryness, itching, and pain during sexual relations.
• Gynecomastia may develop and occasionally persists in patients being treated for hypogonadism
• Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, and ankle swelling. Males should be instructed to report too frequent or persistent erections of the penis and females any hoarseness, acne, changes in menstrual periods or increase in facial hair.

3. Testosterone

Mechanism of Action:

Responsible for normal growth and development of male sex organs and maintenance and maturation of secondary sex characteristics. Also decreases estrogen activity, which aids treatment of some breast cancers.

Indications:

• Androgen replacement therapy in treatment of delayed male puberty
• Male hypogonadism (congenital or acquired)
• Inoperable female breast cancer pts who are 1–5 yrs postmenopausal.

Contraindications and Cautions:

• Hypersensitivity to testosterone.
• Breastfeeding, pregnant or who may become pregnant
• Prostate (known or suspected) or breast cancer in males.
• Depo-Testosterone (additional): Severe cardiac/hepatic/renal disease.

Cautions:

Renal/hepatic/ cardiac dysfunction, pts with history of MI or CAD; conditions influenced by edema (e.g., seizure disorder, migraines).

Metabolism and Half- Life:

Well absorbed after IM administration. Protein binding: 98%. Metabolized in liver. Primarily excreted in urine. Unknown

if removed by hemodialysis. Half- life: 10–100 min.

Drug Interactions:

• May increase hepatotoxic effect of cyclosporine.
• May increase the anticoagulant effect of warfarin.
• May increase Hgb, Hct, LDL, serum alkaline phosphatase, bilirubin, calcium, potassium, sodium, AST.
• May decrease HDL.

Side- Effects:​

Frequent:

Gynecomastia, acne.

Females:​ Hirsutism, amenorrhea, other​ menstrual irregularities; deepening of​ voice; clitoral enlargement (may not​ be reversible when drug is discontinued).​

Occasional:

Edema, nausea, insomnia,​ oligospermia, priapism, male- pattern​ baldness, bladder irritability,​ hypercalcemia (in immobilized pts,​ those with breast cancer), hypercholesterolemia,​ inflammation/pain at IM​ injection site.

Transdermal: Pruritus,​ erythema, skin irritation.

Rare:

Polycythaemia​ (with high dosage), hypersensitivity.​

Nursing Considerations

Baseline assessment

• Establish baseline weight, B/P, Hgb, Hct. Check LFT, electrolytes, cholesterol.
• Wrist X-rays may be ordered to determine bone maturation in children.
• Question history of hepatic/renal impairment, seizure disorder, thromboembolism (CVA, MI, pulmonary embolism).

Intervention/evaluation

• Weigh daily, report weekly gain of more than 5 lb; evaluate for edema.
• Monitor I&O.
• Monitor B/P.
• Assess serum electrolytes, cholesterol, Hgb, Hct (periodically for high dosage), LFT, radiologic exam of wrist, hand (when using in prepubertal children). With breast cancer or immobility, check for hypercalcemia (lethargy, muscle weakness, confusion, irritability).
• Ensure adequate intake of protein, calories.
• Assess for virilization.
• Monitor sleep patterns.
• Monitor for CVA (aphasia, confusion, paraesthesia, hemiparesis, seizures), MI (chest pain, diaphoresis, left arm/jaw pain, increased serum troponin, ST segment elevation), pulmonary embolism (chest pain, dyspnea, hypoxia, tachycardia).
• Monitor electrolyte levels, liver function tests, blood and urine calcium levels, lipid panels, CBC with white cell differential, and semen studies.
• Assess diabetic patient carefully for hypoglycemia.
• Closely monitor neurologic status. Stay alert for sleep apnea.
• Assess for early signs of excessive hormonal effects in females (virilization). If these occur, drug withdrawal may be indicated.

Patient/family teaching

• Regular visits to physician and monitoring tests are necessary.
• Do not take any other medication without consulting physician.
• Maintain diet high in protein, calories.
• Food may be better tolerated in small, frequent feedings.
• Weigh daily; report 5 lb/wk gain.
• Report nausea, vomiting, acne, pedal edema.
• Females: Promptly report menstrual irregularities, hoarseness, deepening of voice.
• Males: Report frequent erections, difficulty urinating, gynecomastia.
• Treatment may cause arterial or venous blood clots; report symptoms of heart attack (chest pain, difficulty breathing, jaw pain, nausea, pain that radiates to the left arm, sweating), stroke (blindness, confusion, one-sided weakness, loss of consciousness, trouble speaking, seizures); DVT (swelling, pain, hot feeling in the arms or legs), lung embolism (difficulty breathing, chest pain, rapid heart rate).
• Instruct patient to immediately report signs and symptoms of liver problems, including nausea, vomiting, yellowing of skin or eyes, and ankle swelling.
• Teach prepubertal male about signs and symptoms of excessive hormonal effects, such as acne, priapism, increased body and facial hair, and penile enlargement.
• Teach postpubertal male about signs and symptoms of excessive adverse hormonal effects, such as erectile dysfunction, gynecomastia, epididymitis, testicular atrophy, and infertility.
• Tell female patient to immediately report signs of masculinization, such as excessive body or facial hair, deepening of voice, clitoral enlargement, and menstrual irregularities.
• Advise female of childbearing age to use barrier contraceptives. Caution her not to breastfeed.
• Tell patient which transdermal patches can be applied to scrotum. Instruct him to apply patch daily to clean, dry skin after removing protective liner to expose drug-containing film. To prevent irritation, instruct him to apply each patch to a different site, waiting at least 1 week before reusing same site.
• Advise patient to apply topical gel once daily to clean, dry skin on shoulder, upper arm, or abdomen. Tell him that after opening packet, he should squeeze entire contents into palm and apply immediately. Instruct him to wait until gel dries before getting dressed.
• Teach patient to place buccal system in comfortable position just above incisor tooth and hold it in place for about 30 seconds to ensure adhesion. Tell him to use opposite side of mouth with each application. Caution him not to dislodge buccal system, especially when eating, drinking, brushing teeth, or using mouthwash. If system doesn’t properly adhere or falls out during 12- hour dosing interval, tell him to discard it and apply new system. If it falls out within 4 hours of next dose, tell him to apply new system and keep it in place until next regularly scheduled dose​.
• Instruct patient to apply topical solution to clean, dry, intact skin of axilla area only and to allow application site to dry completely before dressing.
• Advise patient to wash axilla with soap and water to remove any testosterone residue if direct skin-to-skin contact with another person is anticipated.
• Tell patient drug shouldn’t be used to enhance athletic performance or physique.

4. Methyltestosterone

Mechanism of Action:

Synthetic testosterone derivatives with anabolic & androgenic activity; promoting growth & development of male sex organs & maintaining secondary sex characteristics in androgen-deficient males.

Indications:

• Androgen Deficiency (Male)
• Hypogonadism, Climacteric & Impotence (Male)
• Postpubertal Cryptorchidism (Male)
• Inoperable Breast Carcinoma (Female)
• Postpartum Breast Pain & Engorgement (Female)
• Females: Inoperable metastatic breast cancer 1-5 years postmenopausal; post-partum breast pain & engorgement
• Males: Delayed puberty
• Off-label: Male climacteric impotence

Contraindications and Cautions:

• Males with breast cancer or known or suspected prostate cancer.
• Known or suspected pregnancy.
• Some manufacturers state that methyltestosterone is contraindicated in patients with cardiac, renal, or hepatic decompensation; hypercalcemia; impaired liver function; and in patients who are easily sexually stimulated.

Cautions

• Cardiac disease, hepatic disease, renal disease, elderly
• Hypercalcemia may occur in patients with breast cancer
• Risk for jaundice, cholestatic hepatitis, abnormal liver function tests, and potentially fatal hepatic peliosis- discontinue if any of these occur.

Metabolism and Half- Life:

• Half-Life: 10-100 min; Peak Plasma Time: 1-2 hr
• Bioavailability: absorbed from GI tract & oral mucosa; Protein Bound: 98%
• Metabolism: less extensively undergoes first-pass hepatic metabolism than testosterone, suitable for PO admin
• Excretion: Urine: 90%; Feces: 6%

Drug Interactions:

• Anticoagulants, oral – May potentiate the action of oral anticoagulants and decrease anticoagulant requirements
• Insulin- May decrease blood glucose concentrations in patients with diabetes
• Oxyphenbutazone- Possible increased serum concentrations of oxyphenbutazone
• Tests for thyroid function – Possible decreased thyroxine-binding globulin concentrations, resulting in decreased total serum thyroxine (T₄) concentrations and increased resin uptake of triiodothyronine (T₃) and T_4. Free thyroid hormone concentrations remain unchanged. May decrease protein-bound iodine (PBI) concentrations.

Side- Effects:

• Edema
• Acne
• Breast soreness
• Priapism
• Menstrual irregularities
• Virilization
• Edema with or without congestive heart failure
• Gynecomastia
• Suppression of clotting factors II, V, VII & X, Erythrocytosis​
• Cholestatic jaundice syndrome​
• Neoplasm of liver​
• Anaphylaxis​

Nursing Considerations

Monitoring:

• Periodic liver function tests should be performed
• Prepubertal males should have X-ray examinations of bone age every 6 months
• Periodically evaluate hemoglobin and hematocrit for polycythemia, especially with high doses
• Women should have frequent determinations of urine and serum calcium levels
• Androgen therapy should be used very cautiously in children and only by specialists aware of the effects on bone maturation.
• Prior to initiating, confirm hypogonadism diagnosis by ensuring serum testosterone concentrations have been measured in the morning on at least 2 separate days and these serum testosterone concentrations are below the normal range.
• Use of androgen therapy in women should be made by an oncologist with expertise in this field; androgen therapy occasionally appears to accelerate disease.

Patient advice:

• Female patients should be instructed to report signs of virilization such as deepening voice, hirsutism, acne, clitoromegaly, and/or menstrual irregularities.
• Male patients should be instructed to report too frequent or persistent penile erections.
• All patients should be instructed to report signs and symptoms of jaundice or edema.
• Patients should understand this drug has been associated with venous thromboembolic events; they should be instructed to contact their healthcare provider promptly if signs or symptoms of DVT or PE develop.
• Patients should understand that this drug has been subject to abuse; steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions.

REFERENCES

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