GnRH Agonists

抗雄激素 A

GnRH Agonists (GnRH 激动剂)

GnRH Agonists (Leuprorelin, Goserelin, Triptorelin, etc.)

Subcutaneous / Intramuscular Injection · Nasal Spray · Implant

GnRH Agonists are the most effective anti-androgen available, suppressing testosterone to castrate levels (< 50 ng/dL) by shutting down the hypothalamic-pituitary-gonadal axis. Both the Endocrine Society 2017 and WPATH SOC 8 recommend their use. When accessible, GnRH agonists are the ideal anti-androgen choice.

Pharmacology

How They Work

GnRH agonists act at a fundamentally different level than other anti-androgens — they target the upstream control center of hormone production ^[1] :

1. Flare-Up Phase: For the first 1-2 weeks, the drug overstimulates pituitary GnRH receptors, causing a transient spike in LH/FSH and testosterone.
2. Receptor Desensitization: Continuous stimulation causes pituitary GnRH receptors to downregulate and become unresponsive.
3. Total Suppression: Within 2-4 weeks, LH/FSH output ceases, dropping T to castrate levels (< 50 ng/dL).

This mechanism suppresses T directly and reliably — without the hepatotoxicity risk of CPA or the hyperkalemia risk of spironolactone ^[2] .

T Suppression Compared to Other Anti-Androgens

Anti-Androgen	Mechanism	T Suppression	Main Limitation
GnRH Agonists	HPG axis shutdown	~95% (< 50 ng/dL)	Extremely expensive; injection required
CPA 5-12.5mg	AR antagonism + progestogenic feedback	~90% (female range)	Meningioma risk (≥25mg)
Spironolactone 100-200mg	Weak AR antagonism	~30-50% (often insufficient)	Hyperkalemia; unreliable T suppression
Bicalutamide 50mg	Pure AR antagonism	T may increase	Hepatotoxicity; requires monitoring

Available Formulations

Injectable Forms

Drug	Brand Names	Dose	Interval	Route	Self-Administration
Leuprorelin	Lupron / Eligard / Prostap	3.75mg / 11.25mg / 22.5mg / 45mg	Monthly / 3-month / 6-month	SubQ or IM	Some SubQ forms can be self-injected
Goserelin	Zoladex	3.6mg / 10.8mg	Monthly / 3-month	SubQ implant (abdomen)	Requires clinical administration (16G needle)
Triptorelin	Decapeptyl / Trelstar	3.75mg / 11.25mg / 22.5mg	Monthly / 3-month / 6-month	IM injection	Requires clinical administration

Non-Injectable Forms

Drug	Brand	Form	Administration	Advantage	Limitation
Buserelin	Suprefact	Nasal spray	2-3 sprays daily	No injection needed	Compliance burden (multiple daily doses)
Nafarelin	Synarel	Nasal spray	2-3 sprays daily	Non-invasive; ~95% T reduction	Limited global supply
Histrelin	Supprelin LA	SubQ implant rod	Surgical insertion in upper arm; lasts 12 months	Once-yearly; best compliance	Very expensive; requires surgical insertion/removal

Administration Guide

Subcutaneous Injection (Leuprorelin, etc.)

Most GnRH agonists are administered via subcutaneous or intramuscular injection. Some formulations (e.g., leuprorelin SubQ) can be self-administered after nurse training ^[1] .

Injection Site Selection:

• Primary: Abdomen, approximately 5cm lateral to the navel (avoid 2cm around navel)
• Alternative: Anterior outer thigh, mid-section
• Rotation: Alternate sites each injection; maintain at least 3cm between injection points; avoid areas with lumps or bruising

Subcutaneous Injection Steps:

1. Prepare: Wash hands. Bring refrigerated medication to room temperature (15-30 minutes). Check expiry date and solution appearance.
2. Clean: Swab injection site with alcohol prep pad. Allow to air-dry completely.
3. Pinch: Using your non-dominant hand, pinch a 2cm fold of skin.
4. Insert: Insert needle at 45-90° angle quickly and firmly, burying the needle fully (1-2cm depth).
5. Inject: Depress plunger slowly over ~30 seconds. Do not rush.
6. Withdraw: Release skin, then withdraw needle swiftly. Press dry cotton ball on site for 15 seconds (do not rub).
7. Dispose: Place needle in sharps container. Record date and injection site.

Goserelin (Zoladex) Note

Zoladex uses a thick pre-loaded syringe (approximately 16G) that implants a solid depot pellet beneath the abdominal fat. This should always be administered by a healthcare professional.

Indian GnRH Lyophilized Powder Reconstitution (Lupride Depot etc.)

Lupride Depot (leuprorelin) from India is commonly obtained in transgender communities due to its significantly lower cost compared to domestic equivalents. Lupride Depot comes as a lyophilized powder + diluent two-vial kit that requires reconstitution before injection.

Kit Contents:

• 1 vial of lyophilized powder (white powder containing leuprorelin 3.75 mg)
• 1 vial of diluent (sterile water for injection)
• Syringe and needles (included in some packages)

Reconstitution Steps:

1. Inspect: Confirm both vials are within expiry date; powder should be white to off-white (no discoloration)
2. Wash hands: Thoroughly wash hands with soap and water
3. Disinfect: Swab both vial rubber stoppers with alcohol wipes, allow to air dry
4. Draw diluent: Using a syringe with a drawing needle (18-20G), withdraw all diluent from the diluent vial
5. Inject into powder vial: Slowly inject the diluent along the wall of the powder vial — do not spray directly onto the powder
6. Dissolve: Gently swirl the vial (do not shake vigorously) until powder is fully dissolved. Solution should be clear or slightly opalescent
7. Draw solution: Invert the vial and withdraw all reconstituted solution, expel air bubbles
8. Change needle: Switch to injection needle (SC: 25-27G, IM: 21-23G)
9. Inject: Follow the subcutaneous injection steps described above

Reconstitution Precautions

• Reconstituted solution must be injected immediately — do not store. The reconstituted product contains no preservatives; delay risks bacterial contamination and reduced potency
• Do not shake vigorously: This creates bubbles and may damage drug activity
• If the solution appears visibly cloudy, contains particles, or is discolored, discard it
• If the diluent vial is damaged or seal is compromised, discard the entire kit
• First-time users should seek guidance from someone experienced

Nasal Spray (Buserelin / Nafarelin)

1. Gently blow your nose to clear passages.
2. Shake bottle and remove cap.
3. Tilt head slightly forward; insert nozzle into one nostril.
4. Press nozzle while inhaling gently.
5. Alternate nostrils with each use.
6. Avoid blowing your nose for 30 minutes after administration.

Implant (Histrelin)

The Supprelin LA implant is surgically placed under the skin of the inner upper arm by a healthcare provider. It continuously releases medication for 12 months, after which it must be surgically removed and replaced.

Storage Requirements

Drug	Storage	Notes
Leuprorelin (depot)	Room temperature (below 25°C)	Protect from light and heat
Goserelin (Zoladex)	Room temperature (below 25°C)	Pre-filled syringe; do not freeze
Triptorelin (Decapeptyl)	Refrigerate (2-8°C)	Lyophilized powder; reconstitute before use
Buserelin nasal spray	Room temperature	Use within 28 days of opening

Flare Management

The initial testosterone spike (“flare-up”) after the first GnRH agonist injection is a normal pharmacological response ^[1] .

Flare Timeline

Time	What Happens	Symptoms
Day 0	GnRH agonist injected	—
Day 2-4	T spikes to ~2× baseline	Possible acne, mood swings, libido changes
Day 7-8	T returns to baseline	Symptoms begin to resolve
Day 14-28	T drops to castrate level (< 50 ng/dL)	Full anti-androgen effect established

How to Manage the Flare

Consider Anti-Androgen Cover During Flare

To mitigate flare symptoms during the first injection, you can start a short course of anti-androgen simultaneously or 1 week before ^[2] :

• CPA 12.5mg/day for 2-4 weeks, then discontinue after flare resolves
• Spironolactone 100mg/day for 2-4 weeks (if CPA is unsuitable)
• If you are already on estradiol, the flare’s clinical impact is usually mild
• Subsequent injections do not cause another flare (first injection only)

Never Use GnRH Agonists Without Estradiol

GnRH agonists suppress both testosterone AND endogenous estradiol to near-zero. You MUST co-administer estradiol to prevent severe bone loss, hot flashes, and mood disorders ^[1] .

Missed Dose

• Missed injection: Administer as soon as possible (do not wait for the next scheduled date).
• Adjust schedule: Calculate the next dose from the actual injection date (monthly: +28 days; quarterly: +84 days).
• Delayed by >1 week: T may partially recover. Check T levels 4 weeks after the late injection.
• Missed nasal spray: Use as soon as remembered. Do not double the dose.

Side Effects

Bone Density Loss

Long-term use without adequate estradiol can cause bone density decline ^{[1] [2]} :

• Both T and E2 are essential for bone maintenance
• Key: Maintaining E2 at 100-200 pg/mL substantially mitigates this risk
• DEXA scan recommended for users on GnRH agonists for > 2 years

Injection Site Reactions

• Pain, redness, and induration at injection site (common)
• Goserelin’s 16G needle causes more pronounced discomfort
• Rotate injection sites to minimize reactions

Hot Flashes

• Caused by rapid sex hormone suppression ^[2]
• Adequate estradiol dosing significantly reduces this
• Generally resolves once E2 levels stabilize

Mood Changes

• Some users experience mood fluctuations, especially early in treatment
• Generally milder than CPA’s mood effects
• Improves once hormone levels stabilize

Monitoring

Test	Frequency	Target / Alert	Action
Testosterone (T)	4 weeks post-injection + every 3-6 months	T < 50 ng/dL	If high: assess injection interval/compliance
Estradiol (E2)	Tested with T	100-200 pg/mL	Ensure adequate E2 for bone protection
Bone Density (DEXA)	Baseline + every 1-2 years after 2+ years	T-score > -1.0	T-score < -2.5: osteoporosis — intervention needed
LH/FSH	Optional, first 3 months	LH < 1, FSH < 4.3	Confirm pituitary suppression

Blood draw timing: GnRH agonist depots maintain relatively stable drug levels. Blood can be drawn at any time relative to the injection — no specific timing window required.

GnRH Antagonists: Emerging Alternative

In addition to GnRH agonists, there are GnRH antagonists — drugs that directly block GnRH receptors without the initial flare.

Drug	Brand	Mechanism	Time to Castrate	Advantage	Limitation
Degarelix	Firmagon	Direct GnRH receptor blockade	3-7 days	No flare; faster onset	Monthly SubQ injection; prominent injection site reactions
Relugolix	Orgovyx	Oral GnRH antagonist	~2 weeks	Oral administration; no flare	Daily oral dosing; very expensive; limited transgender evidence

Limited Transgender Evidence

GnRH antagonists are primarily approved for prostate cancer. Evidence for transgender HRT use is limited and they are not yet formally recommended by WPATH SOC 8 or Endocrine Society 2017. Use under experienced medical supervision.

Advantages & Limitations

Advantages

• Strongest, most reliable T suppression: Consistently achieves castrate levels ^[1]
• Excellent safety profile: No hepatotoxicity, no hyperkalemia, no meningioma risk
• Infrequent dosing: Monthly or quarterly injections; excellent compliance
• Reversible: HPG axis recovers after discontinuation (weeks to months); fertility can return
• Guideline-recommended: Endorsed by both ES 2017 and WPATH SOC 8 ^[2]

Limitations

• Prohibitive cost: $1,000-3,000/injection in the US; UK/EU NHS may cover; China ~¥1,000-2,000/month
• Injection required: Cannot be taken orally (nasal sprays have limited availability)
• Access barriers: Prescription required; often prescribed off-label for gender dysphoria
• Initial flare: First injection causes temporary T spike (manageable with anti-androgen cover)
• Bone density monitoring: Long-term use requires DEXA scans; must always co-administer estradiol

When to Consider GnRH Agonists

Recommended when ^{[1] [2]} :

• Finances allow sustained use
• CPA is contraindicated (liver issues, meningioma risk, severe mood effects)
• Spironolactone is intolerable (hyperkalemia risk, renal insufficiency)
• Maximum T suppression reliability is desired
• Adolescent puberty suppression (under specialist supervision)

May not be suitable when:

• Cost is prohibitive
• Regular clinic visits for injections are not feasible
• Severe osteoporosis is present (evaluate bone density first)

品牌图鉴

🇯🇵日本

抑那通 / リュープリン (Lupron)

厂商

武田 (Takeda) / AbbVie

规格

3.75mg / 11.25mg / 22.5mg 注射剂

外观

预填充注射器，白色冻干粉末

日本最常用的 GnRH 激动剂，需皮下/肌肉注射，月剂型或季度剂型

🇨🇳中国

贝依 / 抑那通

厂商

丽珠集团 / AbbVie (中国)

规格

3.75mg / 11.25mg

外观

注射用白色冻干粉末

中国大陆可获取的亮丙瑞林制剂，有国药准字批号，约 1000-2000 元/支

🇬🇧英国

诺雷得 Zoladex

厂商

阿斯利康 (AstraZeneca)

规格

3.6mg / 10.8mg 皮下植入剂

外观

预填充注射器 + 固体缓释棒（16G 粗针）

皮下植入型 GnRH 激动剂，针头较粗，需医护操作。中国大陆有进口，有国药准字批号

🇫🇷法国

达菲林 Decapeptyl

厂商

Ipsen

规格

3.75mg / 11.25mg / 22.5mg

外观

注射用冻干粉末

法国产曲普瑞林，需肌肉注射。中国大陆有进口

🇩🇪德国

Suprefact (布舍瑞林)

厂商

赛诺菲 (Sanofi)

规格

鼻喷剂 100µg/喷 · 注射液

外观

鼻喷瓶 / 注射液

唯一可用鼻喷剂型的 GnRH 激动剂，无需注射。每日 2-3 次喷鼻，全球供应有限

🇺🇸美国

Supprelin LA (组氨瑞林)

厂商

Endo Pharmaceuticals

规格

65µg/天 × 12 个月皮下植入棒

外观

小型柱状皮下植入棒

持续 12 个月的皮下植入棒，一年一次手术更换。价格极高（美国约 $45,000/年），主要用于青春期阻断

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