Anabolic-androgenic steroid effects on libido (Part 1: Men)

Anabolic-androgenic steroid effects on libido (Part 1: Men)

Definitions

Libido: sexual desire or sexual interest that arises out of central arousal and response, manifested as thoughts about sex accompanied by genital response. [1].

Sexual function: a broader concept that encompasses measures of libido (e.g., Male Sexual Health Questionnaire: sexual desire [comprehensive]), as one aspect or component.

Anabolic-androgenic steroids (AAS), or androgens enhance sexual function (by acting on CNS & genital tissues). [2].

Introduction

This is the first article in a two-part series on the topic of androgen effects on libido in men and women. This first article will focus on androgen effects on libido in men (the second part on androgen effects on libido in women). Also, relatedly, nandrolone will be presented as a counterexample to the general androgen enhancement of libido, and the putative mechanisms in its effective hampering of libido and sexual function will be enumerated and discussed. Finally, the neurotransmitter dopamine and its influence on the excitatory system will be discussed, and in particular its pertinent relationship to the nandrolone suppression of libido. This author posits a novel mechanism herein by which nandrolone likely contributes to suppress libido via augmented dopamine metabolism.

In men, the endogenous androgens testosterone (T) and its 5α-reductase product, DHT, exert a clear organizing & activating effect on sexual behavior, including sexual desire (libido) that is traceable to spermarche (the occurrence of first ejaculation) and maturation (puberty in the male is associated with an 18-fold increase in endogenous testosterone concentrations). [1].

Men differ from women broadly with respect to libido. Few would argue, despite some variation and the existence of relative outliers, that men are not characteristically more virile than women. And yet, despite a broad consensus between biological and biomedical researchers, as well as the lay public, that testosterone is implicated in sex differences in libido and indeed enhances libido, there is surprisingly conflicting evidence in the literature on this subject, particularly with respect to differences in and between women. The particular effects of androgen on libido in women is discussed in part two of this series.

Threshold effect

It is clear that TRT (testosterone replacement therapy) administered therapeutically to a hypogonadal man will almost certainly relieve symptoms of low libido, absent some organic pathology in sexual function.

Conceptually, the prevailing medical view is that testosterone concentrations in men is subject to a threshold effect, with an established base-line of normal total testosterone (TT) and free testosterone (fT) concentrations (normal TT 450 – 1,000 ng/dL & fT 1 – 2% of TT), below which adverse effects on libido and sexual function prevail; and above which few behavioral changes manifest.

TRT to relieve symptoms of hypogonadism (including low libido) shows clear and consistent effects, generally increasing the frequency of sexual intercourse and masturbation. Important distinctions of the TRT population are in order, however. First, TRT is often prescribed to older, otherwise healthy men in stable relationships, which naturally increases opportunities for sexual intercourse. TRT is most frequently prescribed in cultures that take a liberal view on masturbation and report its frequency honestly. Indeed, men differ by culture in manifestation of libido as masturbatory behaviors [3]; and the population of AAS or androgen users (e.g., for physique or performance enhancement objectives) may be qualitatively different from those of TRT. Thus, measures of changes to libido by androgen necessarily must be measured in a manner that is not affected by these cultural or socio-relational factors.

Is there truly a “ceiling effect” at endogenous levels, above which androgen has no effect on libido?

Interestingly, the evidence strongly suggests the absence of a theoretical upper limit, or ceiling, for behavioral effects of androgen. Evidence from normal healthy men (the population for whom the prevailing medical view is addressed) suggests either no theoretical upper limit, or at least that if such a ceiling exists, it is far greater than even high-normal endogenous circulating androgen levels:

Anderson and colleagues showed that a 200 mg weekly dose of testosterone enanthate increases sexual interest in normal healthy men. Specifically, the results showed increased scores on the Subscale 2 of the Sexual Experience Scale, which measures the extent to which an individual seeks or allows (rather than avoids or rejects) sexual stimuli of an audiovisual or imaginary kind; it is, therefore, an index of sexual interest independent of interaction with a partner (greater validity that frequency of coitus, as the availability of a romantic partner influence frequency of sexual activities; masturbation frequency is culturally influenced; etc.). [4].

Su and colleagues showed that a 240 mg daily dose of methyltestosterone increased sexual arousal on visual analogue scale (VAS) in normal healthy men. [5].

Moss and colleagues showed that androgen-abusing male athletes engage in a higher frequency of sexual intercourse and achieve a higher number of weekly ejaculations (all subjects had the availability of a sexual partner) than their non-androgen-using counterparts. [6].

Androgen Receptor Function in CNS (males)

Androgen Receptor Knockout (ARKO) models are a useful tool to study the function of T/androgen. In CNS tissue, knocking out the AR (null expression), causes male rodents to behave in a manner devoid of male sexual and aggressive behavior. [7].

This has teleological implications: that it is not purely a social construct that men are expected to, within societal bounds, be the romantic pursuer (ask for a date, rather than the woman); and perhaps even to exhibit aggression in the bedroom (be a gentleman on the streets, but a beast in the sheets). It is likely that evolutionary pressures and the human species’ interest in reproduction relies upon men asserting their sexual role in competition for mates and that this competition necessarily relates to physical prowess. As is so often the case, society interacts with biology – defining the boundaries for male aggression and sexual pursuits.

The Desensitization Hypothesis (to be covered in depth in part two of this series) describes a theoretical model that draws inferences about some likely biological and epigenetic processes that result in behavioral desensitization to androgen in males by the perinatal surge in testosterone (and by inference, the manifestation of potentially maladaptive behaviors if such desensitization is foregone, in adulthood, when T levels increase 18-fold). Specifically, Bancroft and colleagues posit that “Exposure to substantially higher T levels during fetal development and also during the first few weeks postnatally [the perinatal surge] could be responsible for desensitizing the CNS to T effects in the male. Such desensitization would presumably act on the genomic level rather than the receptor stage of hormone action… and in the short-term, both T & DHT exposure results in upregulation of AR. A consequence of such desensitization in the male would be that genetically determined variations in CNS receptor responsiveness to T would be “flattened out,” as well as allowing much higher levels of T from puberty onward without hyperstimulation of CNS mechanisms.” [1].

The apparent libido decrease by nandrolone

One drug in particular that is used clinically and therapeutically in men and women that presents a counterexample to the apparent androgen enhancement of libido is nandrolone. Indeed, it is often associated with reduced libido. [8]. An unspoken – perhaps unsavory – rationale to its use in men with HIV wasting rather than testosterone, is to reduce libido (and therefore, to reduce sexual interactions between gay men in order to reduce the spread of disease).

Hulsbæk and colleagues administered nandrolone in different doses to three groups: (1) men whose total testosterone (TT) ≥11 nmol/L (100 mg nandrolone decanoate every third week), (2) men whose TT <11 nmol/L (200 mg nandrolone decanoate every third week), and (3) women (50 mg every third week), for 12 weeks. The results showed no incidence of increased libido by nandrolone decanoate (0/9 women & 0/3 men; 1 incidence of increased libido was reported in the placebo group, given an inactive oil-based vehicle without androgen). [9].

One avenue by which nandrolone is unlikely to decrease libido is by increasing prolactin. While high prolactin levels in men, as in the case with prolactin-secreting adenomas, are associated with hypogonadal symptoms (i.e., low libido) and even galactorrhea (lactation); nandrolone is not likely to raise prolactin (at least at doses used in common practice). Generally, aromatizing androgen (e.g., testosterone [10], MENT [11]) show a tendency (a trend; rather than a significant effect) to increase serum prolactin as a consequence of their aromatic products (i.e., estrogens) acting as stimulatory factors to the secretion of prolactin from the anterior pituitary [10]. Nandrolone at lower doses appears to have no significant effect on serum prolactin (likely due to sub-normal E2 levels), [12].

Conversely, nonaromatizing androgen (e.g., trenbolone, oxandrolone, etc.) likely reduce serum prolactin. This is an empirical observation based on human bloodwork results, as well as the basis for a prevailing hypothesis, to this author’s knowledge, being first advanced by De Las Heras and colleagues in 1979. [13].:

Since prolactin secretion in the male rat has been reported to be pulsatile (17), analysis of differences between basal prolactin levels based on a single determination may be misleading. An alternative possibility is that some androgens may actually be inhibitory to prolactin secretion. In our studies, the lowest values among all groups were obtained in animals treated with dihydrotestosterone or androstanediol, although the differences never achieved significance. Nolin et al. (11) reported that dihydrotestosterone significantly suppressed prolactin levels in intact female rats.

Factors that are likely to influence nandrolone’s failure to enhance – and even to diminish – libido include [8]:

  • Estrogens: Nandrolone tends to lead to sub-normal estrogen levels in men at therapeutic doses up to 200 mg weekly. After 6 weeks, serum estradiol (E2) was reduced to 11 ± 9 pg/mL at a 100 mg weekly nandrolone decanoate dose, and to 14 ± 4 pg/mL at a 200 mg weekly nandrolone decanoate dose in normal men [14]. The influence of estrogens and estradiol on libido is not established, in men nor women; but there are some indications that suggest an inverse U-shaped curve with respect to estradiol concentrations and libido (with concentrations that are too low & too high causing reductions to libido).
  • 5α-reduction to DHN, a weakened androgen: Nandrolone, unlike testosterone that is amplified to the more potent DHT in CNS & sex tissues by 5α-reductase, is diminished in its androgenic potency in these target organs by yielding DHN (5α-dihydronandrolone). There is corollary evidence that 5α-reductase inhibitors (e.g., dutasteride, finasteride) that reduce amplification of T to DHT are associated with reduced libido in healthy men. [15].
  • Negative feedback (inhibition) of gonadotropins: Nandrolone, lacking the C-19 methyl group of testosterone, has more broad homology for the nuclear receptor superfamily, including the progesterone receptor (PR) given the effects of this modification on its stereochemical properties and conformational shape. It therefore contributes to dysregulate gonadotropin secretion that is under hypothalamic GnRH regulation, which includes the interplay between the secretion of luteinizing hormone (LH) & follicle-stimulating hormone (FSH) from the hypothalamus [positive regulators] & sex hormone-binding globulin (SHBG) and inhibin from the Sertoli cells [negative regulators], and T from the Leydig cell [negative regulator], in a more pluripotent manner than testosterone. Nandrolone serves to dysregulate this regulatory system by acting to:
    • exert negative feedback at the pituitary (LH secretion) via its aromatization to estradiol
    • slow down the rate of hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency by androgenic and estrogenic action
    • dysregulate hypothalamic regulation of T and gonadotropins via KNDy dendron signalling/pulsatility as a progestin or progesterone analogue
    • increase prolactin expression at high doses (via its aromatic product, estradiol) – elevated serum prolactin has a tertiary role in reducing libido (primarily by acting at the hypothalamus). [16].
  • Increased dopamine metabolism (i.e., net breakdown): To this author’s knowledge, this is a novel putative mechanism, never before proposed, for how nandrolone may contribute to reduced libido:Nandrolone increases serum homovanillic acid (HVA) in man [14], reflecting its metabolism (i.e., breakdown), and is likely related to reduced dopamine receptor number.Serum homovanillic acid (HVA) changed significantly in nandrolone decanoate at 100 mg weekly (+17.6 ± 7.7 pmol/L) and nandrolone decanoate at 300 mg weekly (+11.0 ± 3.3 pmol/L) but not in testosterone enanthate at 100 mg nor testosterone enanthate at 300 mg weekly groups [14]. Thus, even at clinical therapeutic dosages, there is a nandrolone effect on dopamine metabolism.Erotic stimuli of an audiovisual nature decreases HVA [17], reflecting increased dopamine activity associated with sexual arousal.It follows then, that if dopamine activity is integral to libido and manifestations of genital response and thoughts about sex arising from central arousal (reflected by decreased HVA), that nandrolone’s effects on dopamine metabolism (reflected by increased HVA) could effect a reduced sexual arousal.

Dopamine and libido

The excitatory system stimulates libido, whereas the inhibitory system stimulates sexual reward, sedation, and satiety. The excitatory system’s core is in brain dopamine (DA) systems (incertohypothalamic and mesolimbic) that link the hypothalamus and limbic systems, and includes melanocortins (MC), oxytocin (OT), and norepinephrine (NE). The inhibitory system contains brain opioid, endocannabinoid (ECB), and serotonin (5-HT) systems that are activated during periods of sexual inhibition and blunt the excitatory system. [18].

Drugs that stimulate activation of hypothalamic DA or that blunt ECB or 5-HT release and/or postsynaptic binding may stimulate libido. [18].

Steroid hormones activate mechanisms of sexual excitation by directing the synthesis of enzymes and receptors for the interactive neurochemical systems of DA, NE, MC, & OT, acting in hypothalamic and limbic brain regions to stimulate sexual arousal, attention, and behaviors. The activation of these excitatory neurochemical systems blunts the influence of inhibitory mechanisms, such as:

  • endogenous opioids released in the cortex, limbic system, hypothalamus, and midbrain during an orgasm or sexual reward (inducing a refractory period and decreased AR expression in the hypothalamic and limbic regions)
  • ECBs that mediate sedation, and
  • 5-HT, that is elevated in those regions to induce refractoriness and sexual satiety. [18].

Estradiol (E2) facilitates DA release, and testosterone (T) potentiates the synthesis of nitric oxide that controls DA release in rats (86 – 88). [18]. Thus, endogenous steroid hormones appear to set the stage – [a priming effect] – for increased DA synthesis and release during periods in which sexual responding might be enhanced. [18].

Behavioral work (e.g., courtship in humans, or crossing of electrified grids to reach a female mate in male rats) to acquire sexual reward, regarded as analogous to libido in observational animal research, is reduced by castration, indicating that gonadal steroid action in brain are necessary for development and/or maintenance of this instrumental behavior. Behavioral work to acquire sexual reward (i.e., libido) is similarly reduced by lesions to the basolateral amygdala, a steroid-concentrating brain region as well as by administration of a dopamine antagonist to the nucleus accumbens within the limbic system. This instrumental behavior is restored in male rats with lesions to the basolateral amygdala by infusion of amphetamine to the nucleus accumbens, indicating that mesolimbic DA release is integral to libido. [18].

There is a definite nexus between steroid hormones (e.g. androgens and estrogens), dopamine activity, and libido. Endogenous sex steroids prime dopamine synthesis and release in key brain centers to support sexual functions, and dopamine stimulates the core excitatory system to govern libido and resultant sexual behavior.

Conclusion

The endogenous androgens (T & DHT) exert a clear effect in men on libido. Supraphysiological androgens generally augment libido in men (even those that are normal and healthy), but chemical modifications to androgens can affect whether particular androgens exert an enhancing or even suppressing effect on libido. The exception generally proves the rule for the statement that androgens tend to augment libido in men.

Testosterone as the primary male sex hormone serves the biological function of controlling the expression of male sexual and aggressive behavior, that must necessarily be connected to physical prowess with respect to adaptive and competitive advantages to promote survival of the human species.

The mechanisms of androgens’ influence on libido involves the neurotransmitter dopamine and its activation of the excitatory system, as well as the indirect effects of estrogens, peripheral amplification versus diminution, gonadotropins of the hypopituitary-pituitary-gonadal axes, and effects on dopamine metabolism, and even tertiary effects on libido by prolactin.

Men are simple, testosterone clearly governs sexual function and libido (with some influence from aromatization to estradiol, particularly in CNS and brain).

In the second part of the series, we will analyze how women are more multifaceted in the dynamics of their hormonal milieu, and the ramifications of hormonal changes from the ovulatory-menstrual cycle; the predominant influence of affect (mood, well-being, and energy) on female libido; the problems that arise from the inherent difficulty in disentangling androgen from estrogen effects in women; The Desensitization Hypothesis and its explanatory power to describe differences in androgen effects on libido in women versus men, and between women; as well as other factors that influence libido and that relate to the difficulties in assigning causality to exogenous androgen effects in females libido.

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