Natesto is an FDA-approved intranasal testosterone gel indicated for testosterone replacement therapy in adult men with classical hypogonadism. Applied inside the nostrils 3 times daily via a metered-dose pump dispenser, it delivers unesterified testosterone across the nasal mucosa to produce rapid, short-lived blood peaks that return toward baseline between doses. Unlike transdermal gels, it carries no boxed warning for secondary skin transfer to women or children, and clinical trials show it maintains gonadotropins and spermatogenesis in most treated men.

This page summarizes what the US and Canadian prescribing information, clinical trials, and regulatory records report about Natesto. It is for educational purposes only and is not medical advice.

Property	Detail
Brand name	Natesto
Active ingredient	Unesterified testosterone (17β-hydroxyandrost-4-en-3-one; C₁₉H₂₈O₂; molecular weight 288.42 g/mol)
Drug class	Endogenous androgen; anabolic-androgenic steroid (AAS)
Formulation	4.5% w/w thixotropic nasal gel in an 11 g multi-dose pump dispenser (60 metered actuations)
Dose per actuation	5.5 mg testosterone in 122.5 mg (0.122 g) of gel
Labeled US dose	11 mg (1 actuation per nostril) 3 times daily, 6 to 8 hours apart (33 mg total daily dose)
Time to peak and half-life	Peak serum concentration in about 40 minutes; elimination half-life 10 to 100 minutes
Regulatory status (checked November 2026)	FDA-approved (NDA 205488, May 28, 2014; label revised July 2025); Health Canada-approved (DIN 02450550); not authorized by the EMA in the European Union
US controlled substance schedule	Schedule III controlled substance (21 CFR 1308.13)
WADA status	Prohibited at all times, in and out of competition (S1.1 Anabolic Androgenic Steroids)

What it is

Natesto is a prescription nasal gel formulation of native, unesterified testosterone (PubChem CID 6013). Whereas injectable formulations such as testosterone cypionate, testosterone enanthate, and testosterone undecanoate attach a fatty-acid ester chain to slow release from an oil depot, and oral testosterone undecanoate relies on intestinal lymphatic absorption, Natesto delivers unmodified testosterone (17β-hydroxyandrost-4-en-3-one, formula C₁₉H₂₈O₂, molecular weight 288.42 g/mol) directly across the vascularized lining of the nasal cavity (Natesto label).

The gel is a slightly yellow, non-sterile, thixotropic (shear-thinning) mixture containing 4.5% testosterone by weight suspended in castor oil, oleoyl polyoxylglycerides (apricot kernel oil PEG-6 esters), and colloidal silicon dioxide (Natesto label). Thixotropic gels become fluid when sheared through a pump nozzle and regain viscosity immediately after deposition on the nasal mucosa, helping the dose stay on the lateral wall of the nostril without dripping into the throat. Each 11 g dispenser delivers 60 metered actuations; 1 actuation dispenses 122.5 mg (0.122 g) of gel containing 5.5 mg of testosterone (Natesto label).

Once absorbed into the systemic circulation, testosterone binds to sex hormone-binding globulin (SHBG, about 40%) and albumin, while roughly 2% circulates as unbound (free) hormone (Natesto label). It activates the intracellular androgen receptor directly and serves as a prohormone for 2 active metabolites: dihydrotestosterone (DHT), formed via 5α-reductase in androgen target tissues, and estradiol, formed via aromatase in adipose, bone, and brain tissue. Because the nasal mucosa has low 5α-reductase activity compared with large areas of skin, intranasal administration converts proportionally less testosterone into DHT than transdermal testosterone gel or topical testosterone cream (Mattern et al., Aging Male 2008; Natesto label).

In a preclinical mouse study using radiolabeled hormone, roughly 75% of an intranasal testosterone dose entered the systemic bloodstream, while whole-brain concentrations reached levels about 2 times as high as after an equal intravenous dose, with roughly 66% of brain uptake occurring via direct nose-to-brain transport toward the olfactory bulb and hypothalamus (Banks et al., J Drug Target 2009). Whether direct nose-to-brain transport occurs to a clinically meaningful extent in humans has not been established.

Regulatory status and approved indication

The US Food and Drug Administration (FDA) approved Natesto under New Drug Application (NDA) 205488 on May 28, 2014 (Drugs@FDA NDA 205488). The product was developed by Trimel Biopharma (later renamed Acerus Pharmaceuticals Corporation) and has been distributed in the US through commercial partners including Endo Pharmaceuticals and Aytu BioPharma. As of November 2026, NDA 205488 remains an active prescription drug product in the US (with its most recent FDA labeling supplement, S-005, approved in July 2025) and is also approved by Health Canada under Drug Identification Number (DIN) 02450550 (Natesto label). As of November 2026, Natesto is not authorized by the European Medicines Agency (EMA) for marketing in the European Union.

Labeled indication and limitations of use

Under the FDA label, Natesto is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone (Natesto label):

Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and elevated gonadotropins — follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Hypogonadotropic (secondary) hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low serum testosterone alongside normal or low gonadotropin concentrations.

Prior to initiating Natesto, the FDA label specifies that the diagnosis of hypogonadism must be confirmed by ensuring that serum testosterone concentrations have been measured in the morning on at least 2 separate days and that these concentrations are below the normal range (Natesto label).

The label includes 3 explicit limitations of use (Natesto label):

Safety and efficacy of Natesto in men with “age-related hypogonadism” (also called late-onset hypogonadism) have not been established.
Safety and efficacy in males under 18 years old have not been established.
Safety and efficacy in men with a body mass index (BMI) over 35 kg/m² have not been established.

Absence of secondary transfer boxed warning

Transdermal testosterone gels and solutions applied to the shoulders, upper arms, or abdomen carry an FDA boxed warning regarding secondary exposure of women and children through skin-to-skin contact or contaminated clothing, which can cause virilization in children. Because Natesto is deposited inside the nostrils rather than on external skin, its FDA prescribing information does not carry a boxed warning for secondary transference (Natesto label).

Labeled dosing and administration

In the US, the FDA-labeled dosage of Natesto is fixed at 11 mg of testosterone (2 pump actuations: 1 actuation of 5.5 mg into each nostril) administered intranasally 3 times daily — morning, afternoon, and evening, preferably 6 to 8 hours apart — for a total daily dose of 33 mg (Natesto label). At 6 actuations per day, a single 60-actuation dispenser lasts 10 days.

The labeled administration sequence requires patients to (Natesto label):

Prime the pump before initial use by inverting the dispenser over a sink and depressing the pump 10 times, discarding any gel into the sink and wiping the tip clean with a dry tissue.
Blow the nose completely before each application.
Place the index finger on the pump, tilt the head slightly backward, and insert the actuator tip into 1 nostril until the finger touches the base of the nose, angling the tip outward so the opening touches the lateral (outer) wall of the nostril.
Slowly depress the pump until it stops, wiping the tip along the inside lateral wall while withdrawing it so the gel transfers fully onto the nasal lining.
Repeat in the opposite nostril using the other hand, then press the nostrils together just below the bridge of the nose and massage lightly.
Refrain from blowing the nose or sniffing for 1 hour after dosing.

Serum monitoring and continuation rules

Unlike transdermal gels or oral capsules that use multiple dose tiers, the US label does not include a dose-titration schedule. Instead, it instructs clinicians to measure total serum testosterone periodically starting 1 month after initiating therapy (Natesto label):

If total serum testosterone consistently exceeds 1,050 ng/dL, the patient should discontinue Natesto.
If total serum testosterone is consistently below 300 ng/dL, the patient should be directed to an alternative treatment.

In contrast, both the pivotal trial and Canadian clinical practice also evaluated a starting regimen of 11 mg 2 times daily (22 mg/day) with optional titration to 11 mg 3 times daily (33 mg/day) based on symptoms and blood levels (Rogol et al., Andrology 2016; Lee et al., Can Urol Assoc J 2019).

Pharmacokinetics

Ultradian absorption and rapid clearance

Natesto produces an ultradian (pulsatile) pharmacokinetic profile characterized by fast absorption after each intranasal dose and rapid return toward endogenous baseline before the next dose (Natesto label; Mattern et al., Aging Male 2008). After intranasal application, serum testosterone reaches its peak concentration (Tmax) in approximately 40 minutes, and the elimination half-life of circulating testosterone ranges from 10 to 100 minutes (Natesto label). About 90% of a testosterone dose is excreted in the urine as glucuronic and sulfuric acid conjugates, and about 6% is excreted in the feces, mostly in unconjugated form (Natesto label).

In an early Phase 2 pharmacokinetic study of 8 hypogonadal men (baseline testosterone 130.8 ± 87.4 ng/dL) given single intranasal doses of 7.6, 15.2, or 22.8 mg, followed by a 14-day study in 21 severely hypogonadal men (20 with baseline testosterone below 50 ng/dL and 1 at 152 ng/dL) given 7.6 mg 2 or 3 times daily, dosing 3 times daily kept the 95% confidence interval of average serum testosterone within the physiological reference range while preserving peaks and troughs (Mattern et al., Aging Male 2008).

In the pivotal 90-day US trial, 69 hypogonadal men in the 11 mg 3-times-daily (33 mg/day) arm completed full 24-hour pharmacokinetic sampling at Day 90 (Natesto label):

Parameter	Day 90 value (n = 69, 11 mg 3 times daily)	Source
24-hour average concentration (Cavg, mean ± SD)	421 ± 116 ng/dL	Natesto FDA label (Table 3)
Maximum concentration (Cmax, mean ± SD)	1,044 ± 378 ng/dL	Natesto FDA label
Minimum concentration (Cmin, mean ± SD)	215 ± 74 ng/dL	Natesto FDA label
Time to peak after dose (Tmax)	Approximately 40 minutes	Natesto FDA label
Patients reaching Cavg 300 to 1,050 ng/dL (PK population)	90% (95% CI 83% to 97%)	Natesto FDA label (Table 2)
Patients with Cmax above 1,500 ng/dL	15.9%	Natesto FDA label
Patients with Cmax between 1,800 and 2,500 ng/dL	1.4%	Natesto FDA label
Patients with Cmax above 2,500 ng/dL	0%	Natesto FDA label
Mean DHT-to-testosterone ratio at Day 90	0.09	Natesto FDA label

At Day 90, serum DHT rose in parallel with total testosterone but stayed within the normal reference range, yielding a mean DHT-to-testosterone ratio of 0.09 (Natesto label). By comparison, transdermal testosterone gels typically produce DHT-to-testosterone ratios of roughly 0.23 to 0.33 because skin contains high levels of 5α-reductase.

Preservation of endogenous baseline production

A post-hoc analysis of the Phase 3 cohort stratified men by baseline endogenous testosterone levels, including men with severe baseline deficiency below 100 ng/dL (Gronski et al., J Endocr Soc 2019). Peak concentrations (Cmax) after a Natesto dose were nearly identical across all baseline severity groups at Days 30 and 90, whereas the 24-hour average concentration (Cavg) retained a slight positive relationship with pre-treatment baseline levels (Gronski et al., J Endocr Soc 2019). Because serum concentrations fall back toward baseline between doses, endogenous hypothalamic-pituitary-gonadal (HPG) axis activity continues during the inter-dose troughs rather than being completely replaced by a continuous exogenous hormone level (Gronski et al., J Endocr Soc 2019).

Effect of allergic rhinitis and nasal decongestants

Because Natesto absorbs across the nasal mucosa, nasal inflammation affects bioavailability. In an open-label, 3-way crossover study of 18 men with seasonal allergic rhinitis exposed to ragweed pollen in an environmental challenge chamber while taking 33 mg/day of Natesto, symptomatic allergic rhinitis reduced 24-hour serum total testosterone exposure by 21% to 24% (and pre-dose trough concentrations by 21% to 25%) compared with the asymptomatic state (Natesto label; Rogol et al., Can Urol Assoc J 2018). Co-administering the nasal decongestant spray oxymetazoline 30 minutes before Natesto did not meaningfully alter absorption compared with untreated allergic rhinitis, changing mean 24-hour area under the curve (AUC) by −2.6% and mean Cmax by −3.6% (Natesto label; Rogol et al., Can Urol Assoc J 2018). The FDA label states that Natesto should not be co-administered with nasal sprays other than sympathomimetic decongestants (such as oxymetazoline), and that patients experiencing severe rhinitis should temporarily discontinue Natesto until symptoms resolve (Natesto label).

Pivotal clinical trial and efficacy data

Phase 3 randomized trial (NCT01446042)

FDA approval was based on a 90-day, multicenter, open-label, randomized Phase 3 trial conducted at 39 US centers in 306 hypogonadal men with morning total testosterone of 300 ng/dL or lower (mean age 54.4 years, range 28 to 80 years; mean BMI 29.8 kg/m²) (Rogol et al., Andrology 2016; Natesto label). Participants were randomized to either:

Fixed 3-times-daily arm (n = 78): 11 mg 3 times daily (33 mg/day) throughout the 90-day treatment period.
Titration arm (n = 228): 11 mg 2 times daily (22 mg/day) from Day 1 to Day 45, with adjustment to 11 mg 3 times daily (33 mg/day) at Day 45 if 24-hour Cavg at Day 30 was below 300 ng/dL.

Following the 90-day efficacy period, patients could enter 2 sequential safety extension periods of 90 days (up to 180 days total) and 180 days (up to 360 days total) (Rogol et al., Andrology 2016; Natesto label).

At Day 90, 90% (66 of 73 evaluable patients; 95% CI 83% to 97%) of men in the fixed 33 mg/day arm achieved a 24-hour Cavg within the normal eugonadal range of 300 to 1,050 ng/dL, compared with 68% (135 of 200; 95% CI 61% to 74%) in the titration arm and 73% (200 of 273; 95% CI 68% to 79%) across the combined intent-to-treat population (Rogol et al., Andrology 2016; Natesto label). In the per-protocol analysis, 91% of the 3-times-daily arm and 70% of the titration arm (76% overall, 180 of 237 men) reached the normal range (Rogol et al., Andrology 2016). Because the fixed 33 mg/day regimen met the FDA efficacy threshold whereas the 22 mg/day starting arm did not, the FDA approved only the 11 mg 3-times-daily (33 mg/day) dose in the US (Natesto label).

In secondary endpoints of the Phase 3 trial, treatment significantly improved International Index of Erectile Function (IIEF) scores across all 5 domains by Day 30 and maintained those improvements through Day 90, alongside significant improvements in positive and negative mood scores (Positive and Negative Affect Schedule, PANAS), lean body mass, and bone mineral density over the extension periods (Rogol et al., Andrology 2016).

Canadian symptom-based titration study (MY-T study)

In Canada, where a 22 mg/day (11 mg 2 times daily) starting dose is permitted, the multicenter MY-T study evaluated treatment satisfaction and symptom response in treatment-naive and previously treated hypogonadal men initiated on 22 mg/day for 90 days (Lee et al., Can Urol Assoc J 2019). At Day 90, 77.0% of participants achieved normal serum testosterone concentrations, and the mean quantitative Androgen Deficiency in the Aging Male (qADAM) symptom score improved from 30.8 at baseline to 35.5 (P below 0.001) (Lee et al., Can Urol Assoc J 2019). At Day 90, physicians up-titrated 37% of participants to 33 mg/day for an additional 30 days, which did not produce a statistically significant further change in qADAM score (Lee et al., Can Urol Assoc J 2019).

Published data on sperm parameters and gonadotropins

Long-acting injectable, pellet, and transdermal testosterone preparations maintain continuously elevated serum testosterone and estradiol levels, which suppress hypothalamic gonadotropin-releasing hormone (GnRH) pulsatility and pituitary LH and FSH secretion. That suppression lowers intratesticular testosterone and frequently causes severe oligospermia or azoospermia (absence of sperm in the ejaculate). Because Natesto has an elimination half-life of 10 to 100 minutes and is cleared between doses, pulses of endogenous GnRH, LH, and FSH secretion can persist during the inter-dose troughs (Ramasamy et al., J Urol 2020; Kavoussi et al., Andrologia 2022). Clinical studies have examined how this pulsatile profile affects gonadotropins and semen parameters.

Phase 4 prospective trial in reproductive-age men (Ramasamy et al., 2020)

A single-center, open-label Phase 4 trial at the University of Miami enrolled 60 symptomatic hypogonadal men aged 18 to 55 years (mean age 37.5 ± 7.2 years, mean BMI 30.6 ± 5.6 kg/m², mean baseline total testosterone 231.8 ± 58 ng/dL) with a baseline total motile sperm count (TMSC) of at least 5 million (mean baseline TMSC 42.9 ± 41.0 million) and treated them with Natesto 11 mg 3 times daily (33 mg/day) for up to 6 months (Ramasamy et al., J Urol 2020). In total, 44 men completed 3-month follow-up and 33 completed 6-month follow-up (Ramasamy et al., J Urol 2020):

Testosterone restoration: 90.9% (30 of 33 men at 6 months) reached normal serum total testosterone above 300 ng/dL (Ramasamy et al., J Urol 2020).
Gonadotropins (LH and FSH): Median FSH and LH decreased modestly from baseline (P = 0.03), but stayed within the normal adult reference range in 81.8% of men for FSH and 72.7% of men for LH at 6 months (Ramasamy et al., J Urol 2020).
Sperm parameters: TMSC above 5 million was preserved in 88.4% of evaluated men at 3 months and 93.9% at 6 months, with 95.0% overall maintaining a TMSC above 5 million at completion (Ramasamy et al., J Urol 2020). Mean changes in sperm concentration from baseline were not statistically significant at 3 months (−4.1 million/mL, P = 0.193) or 6 months (−5.5 million/mL, P = 0.081) (Ramasamy et al., J Urol 2020).
Outliers: 1 participant (1.7% of enrolled men; 2.5% of men with follow-up semen analysis) became azoospermic and recovered after discontinuing treatment, and 3 men (5.0% of enrolled; 7.5% of evaluated) developed severe oligospermia below 1 million/mL (Ramasamy et al., J Urol 2020). In addition, 10 participants discontinued due to nasal irritation (Ramasamy et al., J Urol 2020).

Switching from clomiphene citrate to Natesto (Kavoussi et al., 2021)

In a retrospective study of 41 hypogonadal men wishing to preserve fertility who switched from off-label clomiphene citrate (a selective estrogen receptor modulator related to enclomiphene) to Natesto (85.4% maintained on 11 mg 2 times daily and 14.6% titrated to 11 mg 3 times daily), total serum testosterone levels were comparable between clomiphene citrate and Natesto, while serum estradiol — which had risen to nearly 2 times baseline on clomiphene citrate — fell significantly back toward baseline on Natesto (Kavoussi et al., Urology 2021). Mean LH did not differ significantly from baseline, mean FSH remained within the normal clinical reference range, semen parameters showed no significant change after at least 3 months on Natesto, and 92.7% (38 of 41 men) reported improved libido after switching (Kavoussi et al., Urology 2021).

In a report on men switching from clomiphene citrate to Natesto at the same center, the 49 men treated to date had stable gonadotropins and semen parameters, except for one 32-year-old man whose values fell on 11 mg twice daily and recovered toward his earlier values after dose titration to 11 mg in the morning and 5.5 mg in the evening (Kavoussi, Urology 2021).

Recovery of spermatogenesis after switching from long-acting TRT (Kavoussi et al., 2022)

A proof-of-concept study evaluated 27 hypogonadal men (mean age 39 ± 8 years) who had been treated with long-acting testosterone replacement for a mean of 24.3 ± 19 months — 20 on intramuscular testosterone cypionate, 5 on transdermal testosterone gels, and 2 on subcutaneous pellets, including 10 men with documented azoospermia — and transitioned them directly to Natesto (11 mg 2 times daily, with 1 of 27 titrated to 3 times daily) without a washout period (Kavoussi et al., Andrologia 2022).

Endpoint	Prior long-acting TRT (n = 27)	After switching to Natesto (n = 27)	P value / comparison
Total testosterone (mean ± SD)	761 ± 278 ng/dL	643.9 ± 170 ng/dL (at 1 month)	P = 0.0675 (vs long-acting TRT)
Estradiol (mean ± SD)	39.6 ± 19 pg/mL	21.5 ± 8 pg/mL (at 1 month)	P = 0.0001 (vs long-acting TRT; baseline 23.7 ± 10 pg/mL)
FSH (mean ± SD)	Suppressed on long-acting TRT	3.7 ± 4 mIU/mL (at 1 month)	P = 0.519 vs pre-TRT baseline (4.5 ± 5 mIU/mL)
LH (mean ± SD)	Suppressed on long-acting TRT	4.6 ± 5 mIU/mL (at 1 month)	P = 1.0 vs pre-TRT baseline (4.6 ± 4 mIU/mL)
Sperm concentration at 3 months (mean ± SD)	Documented azoospermia in 10 tested men	50.7 ± 36 million/mL (all 27 men); 41.0 ± 27.4 million/mL in the 10 previously azoospermic men	27 of 27 resumed spermatogenesis
Total motile sperm count at 3 months (mean ± SD)	0 in 10 tested azoospermic men	69.1 ± 65 million	Normalized across cohort

All 27 of 27 men recovered gonadotropins into the normal reference range within 1 month and demonstrated active spermatogenesis by 3 months without stopping testosterone therapy or requiring human chorionic gonadotropin (hCG) (Kavoussi et al., Andrologia 2022). However, the FDA label still carries the standard class warning that large doses of exogenous androgens can suppress spermatogenesis through feedback inhibition of pituitary FSH (Natesto label), and individual cases of oligospermia or azoospermia have been documented in clinical trials (Ramasamy et al., J Urol 2020; Kavoussi, Urology 2021).

Nasal side effects and systemic safety

Local nasal adverse reactions

Because the gel is applied inside the nostrils 3 times daily, local upper-respiratory and nasal symptoms are the most common adverse reactions. In the pivotal trial among the 78 men treated with the FDA-approved 11 mg 3-times-daily dose during the 90-day efficacy period, adverse reactions reported in 3% or more of patients included (Natesto label):

Adverse reaction	90-day period (11 mg 3 times daily, n = 78)	Up to 180 days (11 mg 3 times daily, n = 69)	Overall trial safety pool (all doses up to 360 days, n = 306)
Nasopharyngitis	3.8% (3/78)	8.7% (6/69)	8.2%
Rhinorrhea (runny nose)	3.8% (3/78)	7.2% (5/69)	7.8%
Epistaxis (nosebleed)	3.8% (3/78)	4.3% (3/69)	6.5%
Nasal discomfort	3.8% (3/78)	5.8% (4/69)	5.9%
Parosmia (altered sense of smell)	Below 3%	5.8% (4/69)	5.2%
Nasal scab	3.8% (3/78)	5.8% (4/69)	5.2%
Prostate-specific antigen (PSA) increased	5.1% (4/78)	5.8% (4/69)	Reported across extensions
Upper respiratory tract infection	3.8% (3/78)	4.3% (3/69)	4.2%
Bronchitis	3.8% (3/78)	4.3% (3/69)	Below 3.9%
Sinusitis	3.8% (3/78)	Below 4%	Below 3.9%
Headache	3.8% (3/78)	4.3% (3/69)	Below 3.9%
Nasal dryness	Below 3%	Below 4%	4.2%
Nasal congestion	Below 3%	Below 4%	3.9%

Across all 306 men treated at any dose through the extensions, 6 patients (2.0%) discontinued treatment due to adverse reactions (Natesto label). Because of limited data in men with underlying nasal pathology, the FDA label recommends against using Natesto in patients with a history of nasal disorders, nasal or sinus surgery, nasal fracture within the previous 6 months, nasal fractures that caused a deviated anterior nasal septum, mucosal inflammatory disorders (such as Sjögren syndrome), or sinus disease (Natesto label).

Hematocrit, prostate, and cardiovascular safety

Hematocrit and polycythemia: Androgens stimulate erythropoietin and red blood cell production. Across all 306 men in the pivotal Natesto trial, 4 participants (1.3%) developed a hematocrit above 55% (from baselines of 48% to 51%), and 0 participants reached a hematocrit above 58% (Natesto label). The label instructs clinicians to check hematocrit prior to initiation, at 3 to 6 months, and annually thereafter, stopping therapy if hematocrit exceeds 54% until it falls to a safe level (Natesto label).
Prostate-specific antigen (PSA) and benign prostatic hyperplasia (BPH): In the pivotal trial, mean serum PSA increased by 0.2 ng/mL at Day 90, 0.1 ng/mL at Day 180, and 0.2 ng/mL at Day 360 (Natesto label). An elevated PSA (defined as an increase from baseline greater than 1.4 µg/L or a single PSA value above 4.0 µg/L) occurred in 5.1% (4 of 78) of men in the 33 mg/day arm during the 90-day core study (Natesto label).
Cardiovascular outcomes and blood pressure: The July 2025 revision of the Natesto FDA label incorporates findings from the TRAVERSE cardiovascular outcomes trial (conducted with transdermal testosterone gel in hypogonadal men with cardiovascular disease or heightened risk), where major adverse cardiovascular events (MACE) occurred in 7.0% of testosterone-treated men versus 7.3% on placebo (hazard ratio 0.96; 95% CI 0.78 to 1.17), while venous thromboembolism occurred in 1.7% versus 1.2% (deep vein thrombosis 0.6% vs 0.5%; pulmonary embolism 0.9% vs 0.5%) and mean systolic blood pressure rose by 1.0 mm Hg from baseline at 36 months versus a 0.5 mm Hg decrease on placebo (a 1.5 mm Hg between-group difference) (Natesto label).

Contraindications

Natesto is contraindicated in (Natesto label):

Men with carcinoma of the breast or known or suspected carcinoma of the prostate.
Women who are pregnant, because testosterone is teratogenic and can cause virilization of a female fetus.
Patients with known hypersensitivity to testosterone or any excipient in the gel.

How Natesto compares with other testosterone formulations

Compared with intramuscular injections, transdermal gels, and oral capsules, Natesto trades dosing convenience (3 intranasal applications per day) for a short-acting, pulsatile hormonal profile with lower rates of secondary erythrocytosis, reduced conversion to DHT and estradiol, no risk of skin-to-skin transfer, and markedly less suppression of pituitary gonadotropins.

Feature	Natesto (nasal gel)	Transdermal gels (Testogel / AndroGel)	Intramuscular esters (Testosterone cypionate / enanthate)	Oral capsules (Testosterone undecanoate)
Dosing frequency	3 times daily (11 mg per dose; 33 mg/day)	1 time daily on skin (typically 40.5 to 100 mg/day)	Every 1 to 4 weeks intramuscularly (often split weekly)	2 times daily with food
Serum profile	Ultradian pulses (peaks at ~40 min; half-life 10 to 100 min)	Continuous steady state over 24 hours	High post-injection peak followed by multi-day decline	Peaks 2 times daily at ~4 to 5 hours; requires dietary fat
Secondary transfer boxed warning	None (applied inside nostrils)	Yes (FDA boxed warning for skin transfer to women and children)	None	None
DHT-to-testosterone ratio	About 0.09 (normal physiological range)	About 0.23 to 0.33 (elevated due to skin 5α-reductase)	Near physiological	Elevated DHT and DHT undecanoate via gut wall
Gonadotropin and sperm preservation	LH, FSH, and sperm counts maintained in ~88% to 94% of men in 6-month trial	Strongly suppressed in most men	Strongly suppressed; high rate of oligospermia or azoospermia	Suppressed with continuous dosing 2 times daily
Erythrocytosis / hematocrit impact	Low (0% at or above 54% in cross-sectional comparison; 1.3% above 55% in Phase 3)	Moderate	Highest among routes	Low to moderate

In a cross-sectional comparative study at the University of Miami comparing 30 hypogonadal men treated with Natesto (11 mg 3 times daily, 33 mg/day) against 30 matched men treated with intramuscular testosterone cypionate (100 to 200 mg weekly) for at least 3 months, polycythemia (defined as hematocrit of 54% or higher) occurred in 10% (3 of 30) of men on testosterone cypionate and a hematocrit of 50% or higher occurred in 33.3% (10 of 30), compared with 0% (0 of 30) for both thresholds in the Natesto group (Best et al., Can Urol Assoc J 2021). On multivariable linear regression adjusting for age, BMI, smoking history, and treatment duration, intramuscular testosterone cypionate was associated with a 3.24% higher hematocrit (95% CI 0.74% to 5.73%, P = 0.012) than intranasal testosterone (Best et al., Can Urol Assoc J 2021). A subsequent Bayesian network meta-analysis of 29 randomized controlled trials confirmed that intranasal and oral testosterone formulations produce smaller increases in hematocrit than intramuscular injections (Nackeeran et al., J Urol 2022).

Schedule III status and athletic bans

In the United States, Natesto is classified as a Schedule III controlled substance under the Controlled Substances Act (21 CFR 1308.13), the same schedule applied to all prescription testosterone products. Prescriptions are subject to federal and state Schedule III refill limits and prescription-monitoring rules, and the FDA label warns that abuse of testosterone at doses above the approved range can lead to serious cardiovascular and psychiatric adverse reactions as well as withdrawal symptoms (depression, fatigue, irritability, insomnia, and hypogonadotropic hypogonadism) upon abrupt cessation (Natesto label).

In competitive sport, exogenous testosterone in any route of administration is prohibited at all times (both in-competition and out-of-competition) under Category S1.1 (Anabolic Androgenic Steroids) on the WADA 2026 Prohibited List. Because Natesto delivers short-acting bursts of unesterified testosterone, anti-doping laboratories detect exogenous nasal testosterone through urinary steroid profiling (such as changes in the testosterone-to-epitestosterone ratio) and gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS).

Key takeaways

First FDA-approved nasal testosterone gel. Approved on May 28, 2014 (NDA 205488), Natesto delivers 5.5 mg of unesterified testosterone per pump actuation into the nostril, with a labeled US regimen of 11 mg (1 actuation per nostril) 3 times daily for a total of 33 mg/day.
Ultradian, short-acting pharmacokinetics. Serum testosterone peaks in about 40 minutes and clears with a half-life of 10 to 100 minutes, producing a 24-hour average concentration of 421 ± 116 ng/dL at Day 90 and restoring normal average testosterone in 90% of men on the 3-times-daily dose.
No boxed warning for secondary transfer. Because the gel is applied inside the nose rather than on external skin, Natesto does not carry the FDA boxed warning for accidental skin transfer to women or children required on transdermal testosterone gels.
Preserves gonadotropins and sperm in most men. In a 6-month Phase 4 trial of reproductive-age men, 93.9% maintained a total motile sperm count above 5 million at 6 months, and in a switch study of 27 men on long-acting TRT, 100% resumed spermatogenesis within 3 months of transitioning to Natesto.
Lower hematocrit and DHT elevations than injections or skin gels. Cross-sectional and network meta-analysis data show substantially lower rates of erythrocytosis than intramuscular testosterone cypionate, and a physiological DHT-to-testosterone ratio of 0.09.
Nasal irritation and 3-times-daily dosing are the primary trade-offs. Nasopharyngitis, runny nose, nosebleeds, nasal discomfort, scabs, and altered smell occur in roughly 4% to 9% of users, severe allergic rhinitis reduces absorption by 21% to 24%, and the product is not recommended for men with chronic nasal or sinus disease.

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Natesto (Nasal Testosterone)