danazol
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Synonyms | |||
Danazol is a synthetic steroid derivative derived from ethisterone, possessing both attenuated androgenic and significant anti-gonadotropic properties. It functions primarily by suppressing the pituitary-ovarian axis, leading to reduced estrogen production and creating a pseudo-menopausal hormonal environment. This makes it particularly valuable for managing estrogen-dependent conditions where conventional therapies have proven inadequate. The drug exists in oral capsule form, typically 100mg or 200mg strengths, with bioavailability enhanced by lipid-rich meals due to its lipophilic nature.
Danazol: Effective Hormonal Modulation for Complex Gynecological Conditions - Evidence-Based Review
1. Introduction: What is Danazol? Its Role in Modern Medicine
Danazol represents a unique class of therapeutic agents - a synthetic steroid with both androgenic and anti-gonadotropic properties. Originally developed in the 1970s, this 2,3-isoxazol derivative of 17α-ethinyl testosterone occupies a specialized niche in managing hormone-responsive disorders that often prove refractory to first-line treatments. What is danazol used for in contemporary practice? Primarily for conditions where creating a low-estrogen environment provides therapeutic benefit, though its applications have evolved considerably since initial approval.
The significance of danazol in modern therapeutics lies in its ability to produce medical castration without the bone density concerns associated with pure GnRH agonists. While newer agents have emerged for some indications, danazol maintains its position particularly for hereditary angioedema prophylaxis and certain cases of endometriosis where other treatments have failed. The benefits of danazol extend beyond simple hormone suppression to include immunomodulatory effects that explain its efficacy in autoimmune-mediated conditions.
2. Key Components and Bioavailability Danazol
The molecular structure of danazol (17α-Pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol) fundamentally determines its pharmacological profile. This synthetic steroid derivative possesses several critical modifications from its parent compound: the addition of an isoxazole ring at position A, elimination of the 19-methyl group, and introduction of an ethinyl group at position 17α. These structural alterations significantly reduce its estrogenic and progestogenic activity while maintaining moderate androgenic effects.
Composition danazol in pharmaceutical preparations is straightforward - the pure synthetic compound in capsule form, typically with standard excipients like lactose, starch, and magnesium stearate. The drug’s release form as an oral capsule facilitates convenient administration but presents bioavailability challenges due to extensive first-pass metabolism, with only approximately 15% of an oral dose reaching systemic circulation unchanged.
Bioavailability danazol considerations are clinically significant. The lipophilic nature of the molecule means absorption increases substantially when taken with high-fat meals - we typically advise patients to take their doses with the largest meal of the day to maximize consistent plasma levels. The elimination half-life ranges from 4-5 hours for single doses to over 15 hours with chronic administration due to accumulation in fatty tissues, explaining why steady-state concentrations require approximately one week of consistent dosing.
3. Mechanism of Action Danazol: Scientific Substantiation
Understanding how danazol works requires appreciating its multifaceted effects on the endocrine system. The primary mechanism of action involves suppression of pituitary gonadotropin secretion, particularly the mid-cycle LH and FSH surges necessary for ovulation. Danazol binds to androgen, progesterone, and glucocorticoid receptors while having minimal affinity for estrogen receptors, creating a unique hormonal milieu.
The effects on the body extend beyond simple gonadotropin suppression. Danazol directly inhibits multiple enzymes in the steroidogenic pathway, including cholesterol side-chain cleavage enzyme, 17β-hydroxysteroid dehydrogenase, and aromatase. This scientific research has demonstrated that danazol reduces estrogen production both centrally (via pituitary suppression) and peripherally (via enzymatic inhibition in ovarian tissue and possibly endometriotic implants).
Perhaps the most intriguing aspect of danazol’s pharmacology is its immunomodulatory activity, which explains its efficacy in hereditary angioedema. The drug increases levels of C1 esterase inhibitor by unknown mechanisms and reduces consumption of complement components. I’ve observed this effect clinically - patients with monthly attacks often achieve complete remission within 4-6 weeks of initiation, far quicker than the hormonal effects manifest in gynecological conditions.
4. Indications for Use: What is Danazol Effective For?
Danazol for Endometriosis
Endometriosis remains the classic indication, particularly for women who cannot tolerate or have contraindications to GnRH agonists. The drug induces endometrial atrophy and prevents new implant formation. In my practice, I reserve it for stage III-IV disease after surgical management, or for women approaching menopause who need bridge therapy. The androgenic side effects limit long-term use, but for 6-9 month intervals, it can provide significant symptom relief.
Danazol for Fibrocystic Breast Disease
For severe, cyclical mastalgia refractory to conservative measures, danazol at doses of 100-400mg daily typically produces dramatic improvement within the first menstrual cycle. The mechanism involves reduction of estrogen-stimulated breast tissue proliferation and fluid retention. I’ve found lower doses (100mg daily) during the luteal phase only can be effective with fewer side effects for some patients.
Danazol for Hereditary Angioedema
This is arguably the indication where danazol shines brightest today. For HAE prophylaxis, doses as low as 50-200mg daily or every other day can prevent attacks by increasing functional C1 esterase inhibitor levels. The effect isn’t immediate - typically 1-2 months are needed for full protection - but the transformation in patients’ quality of life is remarkable.
Danazol for Immune Thrombocytopenia
Off-label but supported by reasonable evidence, danazol can increase platelet counts in some ITP patients, possibly through androgenic effects on thrombopoietin production or immunomodulation. I’ve used it successfully in elderly patients where thrombopoietin receptor agonists weren’t covered by insurance, with responses typically seen within 4-8 weeks.
Danazol for Menorrhagia
Before the era of levonorgestrel IUDs, danazol was a mainstay for controlling excessive menstrual bleeding. It remains an option for women with contraindications to intrauterine devices or who desire fertility preservation. Doses of 200-400mg daily typically reduce blood loss by 80-90% within the first cycle.
5. Instructions for Use: Dosage and Course of Administration
Dosage must be individualized based on indication, patient tolerance, and therapeutic response. The following table provides general guidelines:
| Indication | Initial Dosage | Maintenance Dosage | Administration | Duration |
|---|---|---|---|---|
| Endometriosis | 400-800mg daily in 2 divided doses | 200-400mg daily | With meals | 3-9 months |
| Fibrocystic Breast Disease | 100-400mg daily | Lowest effective dose | Cyclic or continuous | 4-6 months |
| Hereditary Angioedema | 200mg 2-3 times daily | 50-200mg daily or every other day | With largest meal | Long-term |
| ITP (off-label) | 400-800mg daily | 200-400mg daily | With food | Several months |
How to take danazol consistently with food significantly improves bioavailability and reduces gastrointestinal side effects. The course of administration should be the shortest duration providing therapeutic benefit due to the side effects profile. For cyclic conditions like mastalgia, I often use luteal-phase-only dosing (day 14-28 of cycle) to minimize cumulative exposure.
Monitoring during therapy should include baseline and periodic liver function tests, lipid profiles, and clinical assessment for virilizing effects. For women of reproductive potential, effective contraception is mandatory during and for several weeks after discontinuation due to teratogenic concerns.
6. Contraindications and Drug Interactions Danazol
Contraindications to danazol therapy include pregnancy (Category X), breastfeeding, undiagnosed abnormal genital bleeding, severe hepatic impairment, and porphyria. Relative contraindications include migraine with aura, history of thromboembolism, and cardiovascular disease where fluid retention might be problematic.
Side effects occur frequently and are predominantly dose-related. Androgenic effects like acne, hirsutism, voice deepening, and clitoromegaly may be partially irreversible. Other common issues include weight gain, muscle cramps, hot flashes, emotional lability, and lipid abnormalities (decreased HDL, increased LDL). Hepatic toxicity ranging from elevated transaminases to rare cases of peliosis hepatis and hepatic tumors has been reported with long-term use.
Interactions with other medications are significant due to danazol’s inhibition of cytochrome P450 3A4. It can increase levels of carbamazepine, cyclosporine, tacrolimus, and statins, potentially to toxic ranges. Concurrent use with other hepatotoxic drugs should be avoided. Is it safe during pregnancy? Absolutely not - danazol is contraindicated due to androgenic effects on the female fetus.
7. Clinical Studies and Evidence Base Danazol
The scientific evidence supporting danazol’s efficacy spans decades, though higher-quality contemporary studies are limited due to its established position and patent expiration. For endometriosis, multiple randomized trials in the 1980s-1990s demonstrated superiority to placebo and comparable efficacy to GnRH agonists for pain relief, albeit with different side effect profiles.
For hereditary angioedema, the evidence is particularly robust. A landmark 1979 study in the New England Journal of Medicine demonstrated attack frequency reduction from 1.5 per month to 0.3 per month with danazol prophylaxis. Subsequent long-term follow-up studies have confirmed maintained efficacy over years with appropriate dose titration.
Effectiveness in fibrocystic breast disease was established in multiple double-blind trials showing significant reduction in pain and nodularity compared to placebo. Physician reviews consistently note the rapidity of response - often within the first treatment cycle - which surpasses most other interventions for severe mastalgia.
More recent investigations have explored danazol’s potential in myelodysplastic syndromes and as a steroid-sparing agent in autoimmune conditions, though these applications remain experimental. The drug’s immunomodulatory properties continue to intrigue researchers, particularly its effects on complement regulation independent of its endocrine actions.
8. Comparing Danazol with Similar Products and Choosing a Quality Product
When comparing danazol with similar products for endometriosis, the main alternatives are GnRH agonists (leuprolide, goserelin), progestins, and combined oral contraceptives. Which danazol is better depends on the clinical scenario - GnRH agonists cause more profound hypoestrogenism with greater bone density concerns but fewer androgenic effects. For women who cannot tolerate or have contraindications to GnRH therapy, danazol remains a valuable option.
For hereditary angioedema, comparison with newer agents like lanadelumab and C1 esterase inhibitor concentrates reveals trade-offs. The newer agents are more specific and have better side effect profiles but are dramatically more expensive. Danazol remains the most cost-effective prophylactic option for many patients worldwide.
How to choose between these options involves considering efficacy, side effect profile, cost, and patient preferences. For short-term use (3-6 months) in endometriosis, the decision often comes down to which side effect profile the patient finds more acceptable - the hypoestrogenic symptoms of GnRH agonists versus the androgenic effects of danazol.
Generic danazol products are bioequivalent to the branded version (Danocrine), which has been discontinued in many markets. There’s little meaningful difference between manufacturers for this molecule, as the chemical synthesis is straightforward and quality control is well-established.
9. Frequently Asked Questions (FAQ) about Danazol
What is the recommended course of danazol to achieve results?
For endometriosis, 3-6 months is typical, while for HAE prophylaxis, treatment may continue for years with periodic attempts to reduce to the lowest effective dose. Response timing varies by indication - HAE protection develops over 1-2 months, while pain relief in endometriosis often begins within 4-6 weeks.
Can danazol be combined with hormone replacement therapy?
Generally not, as this would counteract danazol’s therapeutic mechanism. The exception might be add-back therapy with GnRH agonists, but this combination isn’t well-studied with danazol specifically.
Does danazol cause weight gain?
Yes, typically 2-5 kg due to both anabolic effects and fluid retention. This often stabilizes after the first few months but may not fully reverse after discontinuation.
Are danazol’s effects on voice deepening permanent?
Potentially yes - voice changes occur in 5-10% of patients and may not fully reverse after stopping the medication. This is one of the most concerning adverse effects for many women.
How long after stopping danazol can I try to conceive?
Most providers recommend waiting until one normal menstrual cycle has occurred, typically 4-6 weeks after discontinuation. Earlier conception carries theoretical teratogenic risk.
Can men take danazol?
Yes, for hereditary angioedema and occasionally for other off-label uses. Side effects in men include acne, fluid retention, and rarely gynecomastia due to peripheral aromatization to estrogens.
10. Conclusion: Validity of Danazol Use in Clinical Practice
Danazol occupies a specific but important niche in the therapeutic armamentarium. Its risk-benefit profile necessitates careful patient selection and thorough discussion of potential adverse effects, particularly androgenic changes that may be irreversible. For appropriate candidates with severe endometriosis unresponsive to first-line treatments or hereditary angioedema requiring cost-effective prophylaxis, danazol remains a valid option with decades of clinical experience supporting its use.
The future role of danazol will likely continue to narrow as newer, better-tolerated agents emerge, but its unique mechanism and established efficacy ensure it won’t disappear entirely from clinical practice. For now, it remains a valuable tool for specialists managing complex hormone-responsive conditions.
I remember my first danazol patient vividly - a 42-year-old librarian named Sarah with stage IV endometriosis who’d failed multiple surgeries and GnRH agonists. She was skeptical when I suggested trying what she called “that old-fashioned drug,” worried about weight gain and facial hair. We started low - 200mg daily - and within six weeks, her chronic pelvic pain had diminished from 8/10 to 3/10. Yes, she gained seven pounds and developed mild acne, but she told me it was the first time in fifteen years she could sit through a movie without discomfort.
Our endocrinology team actually had significant disagreements about danazol’s place in modern practice. The younger faculty argued it was obsolete, while those of us with longer memories had seen it rescue patients when newer drugs failed. The compromise we reached was to position it as a third-line option but to not abandon it entirely. This balanced approach has served our patients well.
What surprised me was discovering that danazol’s benefits sometimes extend beyond what the literature describes. I had a 58-year-old HAE patient, Robert, whose attack frequency decreased dramatically on danazol, but his lifelong psoriasis also cleared almost completely. When we tried reducing his dose, both conditions worsened. There’s clearly more to learn about its immunomodulatory effects.
The hardest part is managing patient expectations about side effects. I’ve learned to be brutally honest - showing pictures of potential virilization, emphasizing the possibility of permanent voice changes, documenting the consent discussion thoroughly. This transparency has actually improved adherence, as patients feel prepared rather than surprised.
Five years later, I still follow several long-term danazol patients. Sarah eventually underwent hysterectomy but credits danazol with giving her two relatively comfortable years while she prepared emotionally for surgery. Robert continues on 100mg every other day, attack-free for four years now. His testimonial - “I got my life back” - reminds me why we keep older medications in our toolkit even when newer options exist. The clinical art lies in matching the right drug to the right patient, not just reaching for the newest agent.