Androgens

Name: Androgens — Reproductive pharmacology
Creator: LearnDrugs

High-yield Verified · Oct 2026

Testosterone replacement fixes the hormone but turns off the axis that makes sperm. Most of its effects — and side effects — run through DHT, estradiol and the feedback loop.

Nursing view → administration, monitoring and patient teaching

Compare: The androgen axis compared — testosterone, 5α-reductase inhibitors, antiandrogens, abiraterone, GnRH agents and PDE5 inhibitors →

Drugs

testosterone Testim, Xyosted, Jatenzo, Aveed, Depo-Testosterone

methyltestosterone —

danazol —

Mechanism

Testosterone and DHT bind the androgen receptor; in many tissues testosterone acts after reduction to DHT, and the steroid-receptor complex moves to the nucleus to start transcription. Androgens retain nitrogen, sodium and water, increase protein anabolism and stimulate red cell production. Exogenous androgens suppress pituitary LH (and, at large doses, FSH) by negative feedback. Danazol suppresses the pituitary-ovarian axis, lowering FSH and LH, with weak androgenic activity; in hereditary angioedema it raises C1 esterase inhibitor levels.

The hypothalamic-pituitary-gonadal axis

The hypothalamus secretes GnRH, which reaches the anterior pituitary through the portal system and stimulates LH and FSH. LH acts on Leydig cells to increase testosterone production from cholesterol. Testosterone limits its own secretion by negative feedback: it suppresses hypothalamic GnRH and reduces pituitary responsiveness to GnRH. Most circulating testosterone is bound to sex hormone-binding globulin and albumin; only a small free fraction acts in tissues.

The labels classify deficiency by where the axis fails. In primary hypogonadism — testicular failure from cryptorchidism, torsion, orchitis, orchiectomy, Klinefelter syndrome, chemotherapy or toxins — testosterone is low and gonadotropins are above normal. In hypogonadotropic hypogonadism — gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma or radiation — testosterone is low but gonadotropins are normal or low. In Kallmann syndrome, GnRH neurons fail to migrate, and the deficiency comes with hyposmia or anosmia.

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The level of the failure decides the gonadotropins: high in testicular failure, low or normal above it.

Two conversions: DHT and estradiol

In peripheral tissues 5α-reductase converts testosterone to dihydrotestosterone (DHT), which drives formation of the prostate, scrotum and penis, contributes to benign prostatic hyperplasia, and acts on sensitive scalp follicles. In many tissues testosterone’s activity depends on this reduction; DHT binds an intracellular receptor, and the steroid-receptor complex moves to the nucleus to start transcription. 5α-reductase inhibitors (finasteride, dutasteride) block this step and are covered with the antiandrogens.

Aromatase converts testosterone to estradiol: the labels name estradiol and DHT as testosterone’s major active metabolites. Peripheral aromatization explains the gynecomastia of testosterone therapy. Aromatase is the target of the Aromatase inhibitors page.

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Testosterone acts itself, as DHT and as estradiol.

Why replacement suppresses fertility

Exogenous testosterone is sensed by the same feedback loop. It inhibits endogenous testosterone release through feedback inhibition of pituitary LH, and at large doses suppresses spermatogenesis through feedback inhibition of pituitary FSH. So the labels warn of azoospermia and reduced fertility, which may be irreversible. The same suppression explains the testicular atrophy and infertility of anabolic steroid misuse, and the hypogonadotropic hypogonadism that can follow withdrawal after supratherapeutic use.

Replacement is for confirmed deficiency: two low morning testosterone values on separate days. The labels state that safety and efficacy in “age-related hypogonadism” have not been established.

Red cells, blood pressure and the gel box

Androgens stimulate red cell production by enhancing erythropoietic stimulation, which is why men have higher hemoglobin and hematocrit than women. On therapy, a rising hematocrit reflects increased red cell mass, which may increase the risk of thromboembolic events; hematocrit is checked before treatment and therapy is stopped if it becomes elevated. Testosterone can also raise blood pressure, which can increase cardiovascular risk over time.

Gels leave testosterone on the skin, which acts as a reservoir. Their boxed warning is about secondary exposure: children who touched unwashed or unclothed application sites developed virilization — genital enlargement, pubic hair, aggressive behavior and advanced bone age.

Danazol

Danazol, a synthetic steroid derived from ethisterone, suppresses the pituitary-ovarian axis, lowering FSH and LH output, and binds sex hormone receptors; its only other demonstrable hormonal effect is weak androgenic activity. Endometrium — normal and ectopic — becomes inactive and atrophic, and ovulation and cyclic bleeding usually return within 60 to 90 days after stopping. In hereditary angioedema it prevents attacks and raises the deficient C1 esterase inhibitor, which also raises C4.

Its boxed warning starts with pregnancy: exposure in utero can virilize the female fetus, so pregnancy is excluded with a sensitive test immediately before starting and a non-hormonal contraceptive is used; it has caused thromboembolism, peliosis hepatis and hepatic adenoma, and benign intracranial hypertension.

Comparing the drugs

Testosterone products and androgen-related drugs compared

Drug	Form	Pharmacokinetic point	Product-specific hazard	Key counseling
Testosterone gel (Testim)	Topical, shoulders and upper arms	Skin acts as a reservoir; about 10% absorbed over 24 hours	Boxed: secondary exposure → virilization of children	Wash hands, cover the site, wash before skin contact; flammable until dry
Testosterone cypionate (Depo-Testosterone)	IM ester in oil	Esters are absorbed slowly from the oil depot; half-life about 8 days	Contraindicated in serious cardiac, hepatic or renal disease	Deep gluteal IM; never IV
Testosterone enanthate (Xyosted)	SC autoinjector	Subcutaneous injection in the abdomen	Depression and suicidal ideation in trials	Abdomen only; avoid IM or intravascular injection
Testosterone undecanoate (Jatenzo; Aveed)	Oral capsule; long-acting IM	Oral form is taken with food	Aveed boxed: POME and anaphylaxis; REMS	Observe 30 minutes after each Aveed injection
Methyltestosterone	Oral 17-α-alkylated androgen	Less extensively metabolized by the liver than oral testosterone	Cholestatic hepatitis, peliosis hepatis, hepatic neoplasms	Periodic liver function tests
Danazol	Oral synthetic steroid	Food increases its bioavailability	Boxed: pregnancy, thromboembolism, peliosis hepatis, intracranial hypertension	Pregnancy test; non-hormonal contraception; start during menstruation

Pharmacokinetics

Oral testosterone and 17-α-alkylation: Oral testosterone is metabolized by the gut, and 44% is cleared by the liver on first pass. Methyltestosterone, 17-α-alkylated, is less extensively metabolized by the liver, has a longer half-life and is more suitable for oral use — at the cost of hepatotoxicity.
Esters and depots: Testosterone esters are less polar than free testosterone; injected in oil, they are absorbed slowly from the lipid phase. Testosterone cypionate’s half-life after IM injection is about 8 days, while free testosterone’s half-life ranges from 10 to 100 minutes.
Binding and elimination: Most plasma testosterone is protein-bound — to sex hormone-binding globulin and albumin — and only about 2% is free; the free concentration determines its half-life. Testosterone is inactivated mainly in the liver; about 90% of a dose appears in the urine as glucuronide and sulfate conjugates.

Uses & drug choice

Testosterone (Testim, Xyosted, Jatenzo, Aveed, Depo-Testosterone) — testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). Safety and efficacy in men with “age-related hypogonadism” have not been established; Aveed is used only when its benefits outweigh the risks of POME and anaphylaxis
Methyltestosterone — replacement therapy in males with primary or hypogonadotropic hypogonadism; stimulating puberty in carefully selected males with clearly delayed puberty; secondary use in women with advancing inoperable metastatic breast cancer
Danazol — endometriosis amenable to hormonal management; prevention of attacks of angioedema of all types (cutaneous, abdominal, laryngeal) in males and females

Low morning testosterone on two days with high LH and FSH → Primary hypogonadism — testosterone replacement

Testicular failure with gonadotropins above the normal range is a labeled indication.

Low testosterone with low or normal LH and FSH → Hypogonadotropic hypogonadism — testosterone replacement, after evaluating the pituitary and hypothalamus

Gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury, is the other labeled indication.

Hypogonadal man who wants to father a child soon → Discuss fertility before starting testosterone

Exogenous androgens suppress FSH and spermatogenesis and may cause azoospermia; the effect may be irreversible.

Gel user who lives with young children → Strict application-site precautions

The gel box: children have been virilized by secondary exposure.

Hematocrit becomes elevated on testosterone → Stop therapy until it falls to an acceptable level

Increased red cell mass may raise thromboembolic risk.

Hereditary angioedema needing attack prevention → Danazol (labeled), with pregnancy excluded in women

It prevents attacks and raises C1 esterase inhibitor; it is contraindicated in pregnancy.

Adverse effects

■ Boxed warning · Testim (testosterone gel)

Virilization has been reported in children who were secondarily exposed to testosterone gel; children should avoid contact with unwashed or unclothed application sites.

■ Boxed warning · Aveed

Serious pulmonary oil microembolism (POME) reactions and anaphylaxis can occur during or immediately after any injection of testosterone undecanoate, including the first.

■ Boxed warning · danazol

Danazol is contraindicated in pregnancy; thromboembolism, peliosis hepatis and benign hepatic adenoma, and benign intracranial hypertension have been reported.

Polycythemia and venous thromboembolism

Testosterone raises hematocrit; an increase in red cell mass may increase the risk of thromboembolic events, and DVT and PE have been reported.

Blood pressure increases

Testosterone can increase blood pressure, which can increase cardiovascular risk over time.

Prostate: BPH and cancer risk

Men with BPH may have worsening urinary symptoms, and androgens may increase the risk of prostate cancer.

Liver: 17-α-alkylated androgens

Prolonged high-dose use of oral 17-α-alkyl androgens such as methyltestosterone has been associated with peliosis hepatis, hepatic neoplasms, cholestatic hepatitis and jaundice.

Abuse and dependence

Testosterone has been abused, typically at doses above those recommended and with other anabolic androgenic steroids.

Edema, gynecomastia, sleep apnea, lipids

Androgens retain sodium and water; edema, with or without heart failure, can complicate cardiac, renal or hepatic disease.

Depression and mood changes (Xyosted, Jatenzo)

Depression and suicidal ideation have occurred in clinical trials of these products.

Androgenic effects of danazol

Weight gain, acne, oily skin, mild hirsutism, edema and voice change — hoarseness or deepening of pitch — can occur and may persist after stopping.

Azoospermia, testicular atrophy, infertility: Negative feedback suppresses pituitary LH and FSH, so the testis is no longer stimulated.
Erythrocytosis, thromboembolism: Androgens stimulate red cell production; increased red cell mass may increase thromboembolic risk.
Gynecomastia: Peripheral aromatization of testosterone to estradiol.
Worsening BPH, acne, male-pattern hair loss: DHT drives prostate growth and acts on scalp follicles; androgens increase sebum.
Edema: Androgens retain sodium and water.
Cholestatic hepatitis, peliosis hepatis (methyltestosterone, danazol): Hepatotoxicity of 17-α-alkylated androgens; peliosis and adenoma with long-term danazol.
Virilization of a female fetus or exposed child: Androgen action on developing tissues — the basis of the pregnancy contraindications and the gel box.

Interactions

Androgens + insulin or other antidiabetic drugs

Androgens may lower blood glucose and insulin requirements; danazol can instead cause insulin resistance.

Androgens or danazol + warfarin

Anticoagulant effect changes (danazol prolongs prothrombin time) — monitor INR more often, especially when starting or stopping.

Testosterone + corticosteroids

More fluid retention — monitor carefully, particularly with cardiac, renal or hepatic disease.

Testosterone + other drugs that raise blood pressure (including some nonprescription analgesic and cold medicines)

Additional increases in blood pressure.

Danazol + simvastatin, atorvastatin or lovastatin

Higher risk of myopathy and rhabdomyolysis — use with caution.

Danazol + carbamazepine, cyclosporine or tacrolimus

Danazol raises their levels (with more renal toxicity for cyclosporine and tacrolimus) — monitor levels.

Jatenzo + food

It is taken with food.

Contraindications

Testosterone or methyltestosterone — men with carcinoma of the breast or known or suspected carcinoma of the prostate — Labeled contraindication; men treated with androgens may be at increased risk for prostate cancer.
Testosterone or methyltestosterone — women who are pregnant — Labeled contraindication — testosterone can cause virilization of the female fetus.
Xyosted, Jatenzo, Aveed or Depo-Testosterone — hypersensitivity to the product or its ingredients — Labeled contraindication; patients with suspected hypersensitivity to Aveed are not re-treated.
Depo-Testosterone — serious cardiac, hepatic or renal disease — Labeled contraindication — androgens can cause edema with or without heart failure.
Danazol — pregnancy, breastfeeding, undiagnosed abnormal genital bleeding, markedly impaired hepatic, renal or cardiac function, porphyria, androgen-dependent tumor, active or past thrombosis or thromboembolic disease, hypersensitivity — Labeled contraindications — danazol virilizes the female fetus, can induce ALA synthetase (porphyria), retains fluid and has caused thromboembolism.
Testosterone — uncontrolled hypertension use caution — Not recommended: testosterone can raise blood pressure.
Testosterone — benign prostatic hyperplasia, elevated hematocrit, or risk factors for sleep apnea use caution — Use with monitoring: BPH can worsen, red cell mass rises, and sleep apnea may be potentiated.
Testosterone — males under 18 or men with “age-related hypogonadism” use caution — Safety and efficacy have not been established; improper use in the young can accelerate bone age and close the epiphyses early.

High-yield

Cell that LH stimulates to make testosterone Leydig cell

Gonadotropins in primary hypogonadism High (above the normal range)

Gonadotropins in hypogonadotropic hypogonadism Low or normal

Hypogonadotropic hypogonadism with anosmia Kallmann syndrome

Enzyme that converts testosterone to DHT 5α-reductase

Conversion that causes gynecomastia on testosterone Aromatization to estradiol

Why exogenous testosterone causes azoospermia Feedback suppression of pituitary LH and FSH

Hematologic effect monitored on testosterone Rising hematocrit (erythrocytosis)

Boxed warning on testosterone gels Secondary exposure → virilization of children

Boxed hazards of intramuscular testosterone undecanoate (Aveed) Pulmonary oil microembolism and anaphylaxis

Danazol’s two labeled indications Endometriosis; hereditary angioedema prevention

Protein danazol raises in hereditary angioedema C1 esterase inhibitor

Practice questions

Q1A 24-year-old man has small testes, sparse body hair and gynecomastia. Morning serum testosterone is low on two separate days, and LH and FSH are both above the normal range. Karyotype is 47,XXY.

Where is the defect, and what does it mean for testosterone therapy?

A.The hypothalamus — GnRH neurons failed to migrate
B.Peripheral 5α-reductase — testosterone is not converted to DHT
C.The androgen receptor — tissues cannot respond to testosterone
D.The testis — primary hypogonadism, a labeled indication for replacement

Show answer

D. The testis — primary hypogonadism, a labeled indication for replacement — Low testosterone with gonadotropins above the normal range is primary hypogonadism: the testis fails and loss of negative feedback raises LH and FSH. Klinefelter syndrome is the most common congenital cause and is named in the testosterone labels. Failed GnRH-neuron migration is Kallmann syndrome, which lowers LH and FSH. 5α-reductase deficiency gives normal testosterone and LH with low DHT, and androgen insensitivity gives elevated testosterone and LH.

Q2A 31-year-old man who has injected testosterone for 2 years to build muscle and his partner have been unable to conceive. His semen analysis shows no sperm, and his testes are small.

What best explains his azoospermia?

A.Testosterone stimulated hypothalamic GnRH, overdriving the testis
B.Feedback inhibition of pituitary LH and FSH, so the testis is no longer stimulated
C.Testosterone blocked androgen receptors in the testis
D.Testosterone suppressed Leydig cells, but FSH and spermatogenesis are unaffected

Show answer

B. Feedback inhibition of pituitary LH and FSH, so the testis is no longer stimulated — Exogenous androgens inhibit endogenous testosterone release through feedback inhibition of pituitary LH, and at large doses suppress spermatogenesis through feedback inhibition of pituitary FSH; testicular atrophy, subfertility and infertility are reported with anabolic steroid misuse. Elevated testosterone suppresses GnRH rather than stimulating it, and the FSH suppression is precisely what stops spermatogenesis. Testosterone and DHT both bind and activate androgen receptors; neither blocks them.

Q3A 52-year-old man with hypogonadotropic hypogonadism has used testosterone gel for 8 months. His testosterone is in the normal range, but he now has tender enlargement of breast tissue.

Which conversion best explains this effect?

A.Aromatization of testosterone to estradiol
B.Reduction of testosterone to DHT by 5α-reductase
C.Androgen-stimulated red cell production
D.Conversion of testosterone to androstenedione by 17β-hydroxysteroid dehydrogenase

Show answer

A. Aromatization of testosterone to estradiol — Gynecomastia on testosterone is due to peripheral aromatization of testosterone to estradiol, one of its two major active metabolites. DHT, made by 5α-reductase, drives the prostate, external genitalia and scalp follicles. Red cell production explains erythrocytosis, not breast growth. 17β-hydroxysteroid dehydrogenase is the step that converts androstenedione to testosterone in testosterone synthesis; the conversion that makes estradiol is aromatization.

Q4A 27-year-old woman with endometriosis amenable to hormonal management is to start danazol. She is sexually active and asks which contraceptive she should use.

Which plan follows the danazol boxed warning?

A.Start danazol mid-cycle and rely on its suppression of ovulation
B.Use a combined oral contraceptive alongside danazol
C.Skip a pregnancy test because danazol is not teratogenic
D.A sensitive pregnancy test immediately before starting, and a non-hormonal contraceptive during therapy

Show answer

D. A sensitive pregnancy test immediately before starting, and a non-hormonal contraceptive during therapy — Danazol is contraindicated in pregnancy: in utero exposure can cause androgenic effects on the female fetus, including clitoral hypertrophy, labial fusion and ambiguous genitalia. Its boxed warning recommends a sensitive pregnancy test immediately before starting and a non-hormonal method of contraception during therapy, and the label says therapy should begin during menstruation. Relying on ovulation suppression or a hormonal method does not meet that requirement.

More in the Reproductive question bank →

Sources

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Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.