# Exogenous Versus Endogenous Nandrolone in Doping Investigations: A Systematic Literature Review
## 1 Introduction  
Nandrolone, or 19-nortestosterone, is an anabolic steroid originating from testosterone, known for its androgenic and muscle-building effects. It was the first anabolic steroid to be synthesized in 1953. Since 1959, it has been used in clinical practice to promote tissue growth and it is applicable in adjunctive therapy for osteoporosis, anemias, burn injuries, and muscle hypotrophy [1]. Soon, its use became an international drug abuse problem, as athletes discovered its evident anabolic properties, especially in sports requiring greater muscular strength, since it is known to increase muscle mass and strength [2]. Due to these performance-enhancing effects, the World Anti-Doping Agency (WADA) prohibits the use of nandrolone in and out of competition and has included it in its Prohibited List of substances [3]. Despite the evolution of analytical techniques that allow for an increasingly precise determination of urinary levels of nandrolone and its main metabolites, issues relating to the endogenous production of this steroid have yet to be comprehensively evaluated.  
Nandrolone can be administered orally or by intramuscular injection. It is metabolized by extensive oxidative bitotransformation to form glucuronide and sulfate conjugates. The main metabolites detectable in urine are 19-norandrosterone (19-NA), 19-norethiodolanolone (19-NE), and 19-norepiandrosterone [4]. The 19-NA is usually the most predominant urinary metabolite, and, for this reason, the detection of nandrolone is usually centered on the identification of this primary metabolite. One problem related to the identification ofandrolone in anti-doping controls is that this anabolic steroid is produced endogenously by the body, which means traces can be found in the urine of healthy subjects who have not metabolized exogenous nandrolone. It is well documented that during pregnancy, there is an increase in 19-norandrosterone levels in urine [5]. In addition, some contraceptive pills contain norsteroids, such as norethisterone, and can lead to urinary excretion of 19-NA [6]. Another source of contamination is the consumption of meat containing anabolic steroids due to the treatment or the natural production of animals such as boars and stallions [7]. Positive tests can also result from the ingestion of dietary supplements contaminated with steroids and prohormones not included in the list of ingredients [8]. For this reason, the World Anti-Doping Agency has issued a technical document [9] to standardize the analysis of 19-norsteroids associated with nandrolone. For instance, gas chromatography combustion isotope ratio mass spectrometry (GC/C/IRMS) is generally not required when the concentration of 19-NA exceeds 15 ng/mL, except in cases of pregnancy, where the laboratory must report an adverse analytical finding. GC/C/IRMS analysis is required for pregnant individuals if the 19-NA concentration is over 15 ng/mL. Additionally, GC/C/IRMS may be conducted when 19-NA levels range from 2.5 to 15 ng/mL to determine if nandrolone is of endogenous or exogenous origin.  
The aim of this systematic review is to focus on the metabolism of nandrolone, the different factors that affect endogenous production leading to the urinary excretion of this steroid or its metabolites, and the different techniques that can be applied to detect nandrolone and discriminate between the exogenous and endogenous forms. For this purpose, all articles in the scientific literature regarding the above-mentioned issues were evaluated. The ultimate goal of this work is to produce an updated paper containing the main predisposing factors for an increased presence of nandrolone and its metabolites in urine that may lead to positives in athletes. In addition, we identify the main second-level analytical tools that can discriminate between endogenous production and exogenous intake of nandrolone.