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Nasal Testosterone Spray
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Nasal Testosterone Spray - 11-25-2012, 06:41 PM

by Dan Gwartney, M.D.

Nasal Testosterone Spray

Through human history, there has been an awareness of a ‘male factor’ that accounts for the masculine features and character of adult men. During the 1800s, it was demonstrated that the testes (balls) were the source of the male factor, as castrated animals would lose male features that would be restored if another set of testes were re-implanted.1 These early studies merely confirmed what had been known and practiced for centuries, as many cultures castrated the weak males of their livestock herds to allow only the fit to breed, in order to promote the health and production of their meat and milk source. Male slaves were also castrated in some societies in order to do away with any assertiveness, as well as reducing their libido and ability to achieve an erection.

The ‘male factor’ was tentatively identified in the 1930s by screening thousands of gallons of men’s urine, isolating the androgen androsterone.2 Androsterone is a metabolite (breakdown product) of testosterone formed in the liver. A few years later, testosterone was isolated and chemists developed ways of synthesizing the hormone in their labs.2 Shortly thereafter, it was reported that simple modifications to androgens affected the physical and physiological properties of the hormone, allowing a drug to be administered orally or as a long-acting injection; drugs were also designed to be more selective in terms of promoting muscle (anabolic) while having less of an effect on sexual organs (androgenic).
The early direction in androgen-based drug development was to create drugs that were as purely anabolic as possible. Initially, most androgenic anabolic steroids (AAS) were oral. The advent of liver disorders, including malignant cancers in patients receiving AAS treatment for chronic illness, along with the development of more specific drugs (e.g., erythropoietin), resulted in the drugs falling from favor. Injectable AAS have been readily available, but the inconvenience of frequent intramuscular injections and poor patient compliance prohibited their use. Long-acting esters of common AAS (testosterone and nandrolone) are available, but there are few approved indications for the use of nandrolone decanoate. Testosterone undecanoate has not received FDA approval, despite an impressive safety record in other countries.3

The recent history of AAS in the clinical setting is focused on male hormone replacement therapy (HRT). HRT has been a matter of controversy, due to conflicting findings of health benefits and risks in women using HRT following menopause.4 Restricting further comments to male HRT, one sees a field that has been neglected for more than 50 years. The hormonal changes of aging are complex, but following the example of menopausal HRT for women, the foundation of male HRT is restoration of the sex hormone, testosterone, to levels associated with health in an individual. Certainly, competent physicians in the field of anti-aging/aging management will also measure other hormones and markers based on a screening history and physical exam.

Limp Treatments For Low Testosterone

Available options for treating testosterone deficiency are surprisingly limited. Generally speaking, clinicians are allowed to choose from injectable testosterone ester (commonly enanthate), topical gels, and topical patches. Injectable testosterone esters suffer from the extreme variations in testosterone concentration produced, especially in the manner administered. In order to make testosterone (or other AAS) suitable for injection, the steroid molecule is connected to a fatty acid by an ester bond (hence the term testosterone ester). This makes the drug soluble in oil, which is a liquid form of fat that can be injected directly into a muscle (gluteus, deltoid, quad, etc.). Depending on the fatty acid connected to the steroid, the hormone is released quickly or slowly into the circulation (bloodstream). Unfortunately, this release is not consistent. The peak concentration occurs within hours to days, depending on the ester; concentrations then fall steadily until the next injection is given.

Dosing schedules for testosterone esters often result in brief periods of high-normal to supraphysiologic (exceeding the normal range), followed by several days of ‘normal’ circulating concentration, then potentially days of sub-normal concentration (below normal range).5 The fluctuations are intolerable for some and the outcome is certainly not optimal. The long-acting testosterone undecanoate (Nebido) is not yet approved for use in the United States and it appears as though the FDA is erring on the side of caution in its review.

Some professionals are “very surprised and disappointed” at the ponderous and convoluted demands of the FDA.3,6 This is disappointing for clinicians, as Nebido provides a steady and consistent testosterone concentration for six to 14 weeks per injection. Injectable forms of testosterone carry additional risks unrelated to drug pharmacology.7 The act of injecting any substance into the body introduces the risk of infection/abscess, oil embolism, nerve damage, etc.
Topical products avoid many of the risks associated with injectable forms of testosterone, but are less convenient, and certain products have unintended consequences. Unlike injectables that fluctuate up and down dramatically within, sometimes exceeding, the physiologic range, topical formulations provide minor fluctuations due to the lower testosterone content of each dose.5 However, the duration of effect of the topical formulations is much shorter, resulting in once-a-day peaks and a need to re-apply daily. As these fluctuations are not as dramatic, symptoms of the ‘highs and lows’ are not commonly evident when used as directed.

Some patients develop irritating skin reactions to the patches; some do not ‘feel’ the subjective benefits of testosterone replacement therapy when using patches, and a few do not like the fact that they are wearing a patch that may be noticed by others.8 The gels require time to apply and allow the area to dry prior to dressing; some have a more ‘greasy’ feel and there is a risk of transferring clinically relevant amounts of testosterone to a spouse, child or other intimate contact. Case reports have been published documenting children or spouses demonstrating signs of masculinization due to testosterone gel exposure.9
One benefit of the daily patches and gels over long-acting injectable esters is that those forms of testosterone administration more closely mimic the natural pattern of testosterone production. Testosterone concentration fluctuates throughout the day in every man, with small pulses of luteinizing hormone (LH is the regulating hormone produced in the pituitary) boosting the concentration of testosterone up toward the higher end of the normal range.10 The LH signal is created whenever the regulatory center in the brain detects that testosterone concentrations are lingering near the lower end of the normal range. This is done to prevent a state of excess or deficiency by increasing production when available testosterone is low and shutting down the production signal when testosterone is high. This regulation, called negative feedback, places the testes on ‘shutdown’ when AAS are used in supraphysiologic amounts.
Yet, even the gels and patches are not optimal for reproducing the natural pattern of testosterone production, as they peak once and fall throughout the day. Of course, applying topical testosterone more than once daily is a possible solution, but that would be very inconvenient— requiring men to apply patches three times daily would increase production costs for the manufacturer. If one is interested in providing a physiological pattern of frequent pulses of testosterone, an inexpensive and convenient method of administering testosterone remains to be marketed.

Follow Your Nose, To Ease Testosterone Woes

For decades, many different medications have been dosed using a method that would meet the criteria of being cheap, convenient, portable, and simple to use frequently— nasal sprays. Primarily used to deliver symptomatic relief for nasal congestion, nasal sprays have found a place, two places if you count each nostril separately, in over-the-counter pharmaceutical sales. However, in terms of prescription drug sales, there is a glaring near-absence of drugs delivered using nasal sprays. There are several reasons pharmaceutical companies do not develop drugs to be delivered via nasal spray, including but not limited to: absorption limitations, shelf life, patient compliance, social acceptance, and other matters. It is important to understand that the drug in a nasal spray is absorbed across the mucosa (surface) of the nasal cavity and not inhaled into the lungs or trachea (windpipe).

The nasal mucosa is a small area, relatively speaking, and allows for very little drug to be absorbed across its surface. It is also a turbulent area, requiring a drug to either be absorbed rapidly before it is inhaled or expelled (sneezing, exhaling, etc.), or delivered in a viscous vehicle (sticky solution) that adheres to the mucosal surface long enough to allow drug delivery. Most drugs delivered via nasal spray are designed to act locally, meaning they are designed to reduce the congestion or swelling of the nasal mucosa when suffering allergy symptoms or a cold. For a drug to act systemically (in the body) or centrally (in the brain), it has to be potent and fast-acting.
Steroid-based drugs are suitable for delivery across the nasal membrane, due to their physical characteristics. One pharmaceutical company, M et P Pharma AG in Switzerland, is developing such a delivery system for male HRT. The research and development team has published the findings of an early clinical trial in the journal The Aging Male.11 In this study, the testosterone-containing product, Nasobol, was administered first in three different doses to determine the pharmacokinetics of the product. Pharmacokinetics refers to how quickly a drug enters the bloodstream, its peak concentration, how long it provides an elevated blood concentration, the total amount of drug delivered over time, and other measures.

In the first part of the study, eight men with proven hypogonadism (low testosterone) received three different doses of Nasobol. The two lower doses (7.6 and 15.2 mg, respectively) demonstrated good absorption, with approximately 30 percent of the dose present in the blood over a 24-hour period.11 A separate animal study reported 75 percent absorption, with approximately one-third (25 percent) appearing in the blood, with the remainder (50 percent) transferring directly into the central nervous system (brain).12 This suggests that the immediate effect of intra-nasal testosterone on mood and behavior may be more dramatic than anticipated. The maximum blood concentration was reached between 60 and 120 minutes, elevating the testosterone concentration in these hypogonadal men from an average of 130 ng/dL (very low) to 578 and 804 ng/dL, respectively (mid- to high-normal). The highest dose, 22.8 mg, did not increase delivery significantly over the 15.2 mg dose, suggesting that the doses greater than 15.2 mg offer no advantage due to limitations in absorption on a limited surface area. Nasobol maintained an increase in circulating testosterone above baseline (the starting concentration before receiving the drug) for approximately 4 to 6 hours.

The second part of the study followed 21 hypogonadal subjects in two groups for 14 days, given a 7.6 mg Nasobol dose either twice or three times daily. Both groups tolerated the treatment protocol well, with no treatment-related adverse (negative) events reported. While both groups demonstrated dose-related spikes in circulating (blood) testosterone, only the three-times daily group maintained testosterone concentration above the lower limit of the normal range at all recorded times.11 Neither treatment resulted in supraphysiologic concentrations of testosterone or DHT for the groups, but one subject in each group did have peak concentrations in the supraphysiologic range.

An additional set of data was collected in this study, evaluating changes in symptom-related quality-of-life changes in these hypogonadal men. There were no clinically significant findings in this area, possibly due to the questionnaires being designed to diagnose symptoms related to androgen deficiency rather than tracking changes with short-term treatment.
Nasobol will be an interesting addition to the HRT pharmacopeia when it is approved. At this time, recruiting is underway for a Phase II clinical trial, so it is likely that this product will not be available in the United States for three more years at the earliest.13

In my opinion, it is unlikely that Nasobol will make a significant commercial impact in the HRT market for several reasons. First, the twice- to three-times daily regimen is certain to be difficult for many people to comply with over the long term.14 The typical outcome of outpatient (at home) antibiotic therapy lends credence to this hypothesis. Nearly everyone prescribed a once-daily antibiotic will take all the pills as directed. However, when prescribed an antibiotic that needs to be taken three times a day, many people miss one or more doses; remember, most antibiotics are only prescribed for seven to 10 days.

If the goal of Nasobol therapy is to restore long-term testosterone concentration, then compliance is essential. Second, intranasal dosing is socially awkward and may be uncomfortable/annoying for some. These factors will further hinder compliance. Third, it remains to be seen if absorption is consistent when the patient has a runny nose or is congested. The prevalence of allergies, colds and other respiratory symptoms makes this a relevant concern. Fourth, if multiple doses are required daily, the patient would need to carry the applicator with him if he works outside the home. This relates to privacy issues. Hypogonadal men would no more wish to be seen with a Nasobol applicator than young women would wish to have strangers or co-workers see their birth control pills. Sadly, society views male HRT in the same light as AAS abuse by athletes. There are other minor issues that the American marketing partner to M et P Pharma AG would need to address.

Building Muscle, Boosting Sex Drive

Of course, relatively few readers of this magazine are men seeking HRT. Most of the interest in Nasobol relates to its application for improving muscle mass, strength, and affecting mood or sex drive/function. There is actually some promise here, though it is highly unlikely that Nasobol would ever be marketed or approved for such use in eugonadal men (men with normal testosterone concentration).15 It is actually more likely that the delivery technique would be pirated by elite trainers or coaches to improve an athlete’s performance in a manner that would not affect his/her ability to pass a drug test.
Recall that Nasobol provided a reliable peak in testosterone within 60-90 minutes.11 That peak could be timed to coincide with training, competition, or sexual activity to optimize performance.16 If used in a drug-tested event, it is unlikely that a single spike would result in an elevated urine-based drug test. If use is restricted to pre-event only (once-per-week or less), it is unlikely that natural production would be affected or the testosterone:epitestosterone ratio would be elevated. If illicit formulators followed the example of Patrick Arnold’s ‘cream’ product, pirated nasally-administered testosterone formulations could be formulated as a blend of testosterone and epitestosterone, allowing for more frequent use without exceeding the WADA testosterone:epitestosterone cutoff. However, it is unclear what effect chronic (long-term) use would have on a eugonadal adult. In all likelihood, maintaining a supraphysiologic concentration of testosterone via nasal administration would be expensive and inconvenient. This fact may actually play in favor of the product, as it lessens the likelihood of abuse for muscle-building purposes.

One area where both pirated and prescribed products may be used is in sexual enhancement, for both men and women. Testosterone concentrations are believed to be critical in promoting sexual arousal and libido in both men and women.17,18 Currently, there is no FDA-approved product for increasing testosterone for the purpose of restoring sexual desire or arousal in women; testosterone patches designed for this purpose have not been approved by the FDA.

Viagra, and similar drugs, are effective for the majority of men with erectile dysfunction. However, the combination of a testosterone spike, timed appropriately with one of the approved erectile dysfunction drugs (e.g., Viagra), would be very effective in both enhancing the ability to develop and maintain an erection, as well as supporting sexual desire. Unfortunately, there is no data from the M et P Pharma AG studies to confirm or reject this hypothesis.

For the athlete or bodybuilder seeking to enhance his physique, Nasobol does not appear to offer any advantage over the time-proven orals and injectables— other than possibly allowing one to pass a drug test (assuming use is not chronic, or the product is blended with epitestosterone; also, isotope testing would reveal doping if such test is applied). The primary advantage to a eugonadal male seeking a training or performance advantage would be a brief surge in aggression, drive and competitiveness; as well as possibly improving recovery. Many more men and women would be interested in the potential this product would have in promoting sexual desire and/or arousal.

M et P Pharma AG is not developing Nasobol for the purpose of performance enhancement, sports or sexual. It is seeking to develop another option for male HRT that offers a unique advantage, that being testosterone delivery in a physiologic pattern. Whether this product is accepted by consumers and professionals once it passes FDA approval remains to be seen. It would be interesting to see if Nasobol is useful as a sexual aid, either alone or as an adjunct to current erectile dysfunction drugs. Perhaps that is an area where researchers might also direct their efforts.

References:
1. Dotson J, Brown R. The History of the Development of Anabolic-Androgenic Steroids. Pediatric Clinics of North America, 2007;54(4):761-9.
2. Medvei VC. The History of Clinical Endocrinology: A Comprehensive Account of Endocrinology from Earliest Times to the Present Day. Informa HealthCare, New York;1993:223. ISBN-13: 978-1850704270.
3. Turner S. Indevus Pharmaceuticals: Nebido Has Lost Its Libido. SeekingAlpha.com 2008 June 5. Available at Indevus Pharmaceuticals: Nebido Has Lost Its Libido - Seeking Alpha, accessed March 11, 2009.
4. Calleja-Agius J, Brincat MP. Hormone replacement therapy post Women's Health Initiative study: where do we stand? Curr Opin Obstet Gynecol, 2008 Dec;20(6):513-8.
5. Gooren LJ. Advances in testosterone replacement therapy. Front Horm Res, 2009;37:32-51.
6. Pharmpro.com. Indevus Pharmaceuticals Provides Update on NEBIDO(R) NDA Status, Company Expects FDA to Request Additional Safety Study Prior to Approval. Available at Pharmaceutical Processing, accessed March 11, 2009.
7. Zhang GY, Gu YQ, et al. A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men. J Androl, 1998 Nov-Dec;19(6):761-8.
8. Jockenhövel F. Testosterone therapy— what, when and to whom? Aging Male, 2004 Dec;7(4):319-24.
9. de Ronde W. Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies. Hum Reprod, 2009 Feb;24(2):425-8.
10. Wilson JD. The evolution of endocrinology. Clin Endocrinol, (Oxf). 2005 Apr;62(4):389-96.
11. Mattern C, Hoffmann C, et al. Testosterone supplementation for hypogonadal men by the nasal route. Aging Male, 2008 Dec;11(4):171-8.
12. Banks WA, Morley JE, et al. Delivery of testosterone to the brain by intranasal administration: comparison to intravenous testosterone. J Drug Target, 2009 Feb;17(2):91-7.
13. ClinicalTrials.gov. NASOBOL in Hypogonadal Men in Comparison to Testosterone Levels in Normal Healthy Male Volunteers. Available at NASOBOL in Hypogonadal Men in Comparison to Testosterone Levels in Normal Healthy Male Volunteers - No Study Results Posted - ClinicalTrials.gov, accessed March 11, 2009.
14. Jin J, Sklar GE, et al. Factors affecting therapeutic compliance: A review from the patient's perspective. Ther Clin Risk Manag, 2008 Feb;4(1):269-86.
15. van Wingen GA, Zylicz SA, et al. Testosterone increases amygdala reactivity in middle-aged women to a young adulthood level. Neuropsychopharmacology, 2009 Feb;34(3):539-47.
16. Zitzmann M. Testosterone and the brain. Aging Male, 2006 Dec;9(4):195-9.
17. Bancroft J. The endocrinology of sexual arousal. J Endocrinol, 2005 Sep;186(3):411-27.
18. Bolour S, Braunstein G. Testosterone therapy in women: a review. Int J Impot Res, 2005 Sep-Oct;17(5):399-408.


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