The Crucial Difference Between Steroidal and Nonsteroidal Androgens

In the 1960s and 1970s, endocrinology underwent a revolution with the discovery of hormone receptors. For androgens, this era marked a shift from viewing these hormones as diffuse chemical messengers to understanding them as ligandsthat bind specific androgen receptors inside target cellspubmed.ncbi.nlm.nih.gov. This discovery clarified how steroidal androgens (like testosterone) exert their effects, and it opened the door to designing nonsteroidal androgens that could target the same receptors in new ways. The historical development of SARMs (Selective Androgen Receptor Modulators) is rooted in this period; scientists began comparing traditional steroid hormones to novel nonsteroidal compounds. In this article, we explore the key differences between steroidal and nonsteroidal androgens – from chemical structure and mechanisms of action to clinical implications – all within the historical progression of androgen receptor research.

Historical Context: Discovery of Hormone Receptors (1960s–1970s)

The late 1960s saw a breakthrough in hormone research: the androgen receptor (AR) was first identified and characterized as a high-affinity binding protein for testosterone and dihydrotestosterone (DHT)pubmed.ncbi.nlm.nih.gov. Before this, the mechanism of androgen action was murky. The receptor concept, pioneered by researchers like Elwood Jensen for estrogen, was extended to androgens – confirming that androgens work by binding to a specific intracellular receptor rather than by nonspecific biochemical change. This realization was pivotal in distinguishing how different molecules could influence androgenic signaling.

First AR-targeted therapies: With the AR’s discovery, scientists quickly leveraged this knowledge. By screening chemical libraries for AR ligands, they discovered the first antiandrogens. Notably, in the late 1960s, the steroidal compound cyproterone was found to block testosterone’s effects by competing at the ARen.wikipedia.org. Adding an acetate group yielded cyproterone acetate, a steroidal antiandrogen used clinically to this day. This established that steroidal analogs could be designed to antagonize the receptor.
Rise of nonsteroidal agents: Shortly after, researchers sought compounds unrelated to steroids that could modulate the AR. In the 1970s, the first nonsteroidal antiandrogen (flutamide) was discovereden.wikipedia.org. Unlike steroidal drugs, flutamide had a completely different structure yet could bind AR and block its activity without the off-target hormonal effects of steroidal agents. This was a proof-of-concept that nonsteroidal androgens (or antiandrogens in this case) could selectively target the androgen receptor.

These developments in the 1960s–70s set the stage for the historical development of SARMs. By understanding the receptor, scientists realized that steroidal androgens vs. nonsteroidal androgens represented two branches of drug design. Steroid-based molecules had been used for decades (e.g. testosterone itself was first isolated in the 1930s), but now nonsteroidal molecules emerged as a novel approach. The contrast between these classes became increasingly important as pharmacology moved toward more selective androgen receptor modulators.

Chemical Structure Differences Between Steroidal and Nonsteroidal Androgens

Steroidal androgens are characterized by the classic four-ring cyclopentanoperhydrophenanthrene core – the hallmark of all steroid hormones. Testosterone, DHT, and anabolic steroids like nandrolone or stanozolol all share this rigid four-ring backbone. These molecules are essentially modifications of the cholesterol-derived steroid structure. For example, small changes to testosterone’s structure (adding or altering functional groups) produce various anabolic–androgenic steroids; however, the steroid nucleus remains intact.

Nonsteroidal androgens, by contrast, do not contain the four-ring steroid nucleusen.wikipedia.org. Instead, they encompass a wide variety of chemical scaffolds – often completely unrelated to each other except for their ability to bind the androgen receptor. Early nonsteroidal AR ligands included simple aromatic compounds (e.g. flutamide is an anilide), while modern nonsteroidal SARMs often feature complex heterocyclic structures (such as aryl-propionamides, quinolinones, or other novel pharmacophores). These compounds are typically smaller and more flexible in structure than steroidal hormones, allowing chemists to tweak their chemical features extensively. In fact, nonsteroidal ligands are known for their flexibility in structural modification, which enables optimization of receptor binding and selectivity in ways that rigid steroid skeletons cannot easily achieve.

Chemical structures of a steroidal androgen versus nonsteroidal androgens. Top left: Testosterone (a steroidal androgen) with its four-ring structure. Top middle and right: Examples of nonsteroidal SARMs (GSK2881078 and LGD-4033) lacking the steroid rings but designed to fit the androgen receptor. Bottom: Ostarine (a nonsteroidal SARM) and a chemically modified analog, illustrating how diverse functional groups can be incorporated into nonsteroidal androgens. These structural differences underlie distinct receptor interactions and metabolic profiles.

The chemical structure differences directly influence how these molecules interact with the androgen receptor and other proteins:

Receptor binding affinity and selectivity: Steroid-based androgens often bind strongly to AR, but their steroid nucleus can also fit other steroid hormone receptors (like estrogen or progesterone receptors) to some extent, causing cross-reactivity. Nonsteroidal androgens typically have distinct pharmacophores that confer high specificity for ARen.wikipedia.org. By avoiding the steroid template, nonsteroidal compounds can be designed to minimize binding to other receptors, potentially reducing side effects.
Metabolic stability and conversion: The steroid framework is susceptible to metabolic enzymes. Notably, testosterone can be converted by 5α-reductase into DHT (a more potent androgen) and by aromatase into estradiol (an estrogen). These conversions mean a steroidal androgen’s effects can be amplified or altered by metabolites. In the 1960s, the type 2 5α-reductase enzyme was first identified, highlighting the importance of DHT formationpubmed.ncbi.nlm.nih.gov. Nonsteroidal androgens are not recognized by these steroid-converting enzymespmc.ncbi.nlm.nih.gov. A nonsteroidal SARM won’t aromatize to estrogen or convert to a more potent DHT analog – an inherent advantage in avoiding certain side effects like gynecomastia or prostate enlargement.
Lipophilicity and bioavailability: Steroidal androgens are lipophilic and easily cross cell membranes, but unmodified testosterone has poor oral bioavailability (due to first-pass metabolism). Medicinal chemistry has to add substitutions (e.g. 17α-alkylation) to make oral steroidal androgens viable, often at the cost of liver toxicity. Nonsteroidal androgens, being novel small molecules, can be optimized for oral bioavailability without the need for such modifications. Many nonsteroidal SARMs were explicitly designed for oral use, with structures that resist rapid metabolic breakdownpubmed.ncbi.nlm.nih.gov.

In summary, steroidal androgens share a common structural motif that defines their chemistry and biology, whereas nonsteroidal androgens encompass diverse structures engineered to interact with the androgen receptor in a more selective manner. These structural differences are the foundation for the differences in their mechanisms and effects.

Mechanisms of Action: How Steroidal and Nonsteroidal Androgens Differ

Both steroidal and nonsteroidal androgens ultimately target the same androgen receptor, but the way they activate or modulate this receptor can differ markedly. The mechanism of action for any AR ligand involves binding to the receptor’s ligand-binding domain, triggering the receptor to change shape, dimerize, and regulate gene expression. Yet, subtle differences in how steroidal vs. nonsteroidal compounds achieve this can lead to different outcomes:

Full agonists vs. selective modulators: Natural steroidal androgens (testosterone, DHT) are full agonists of the AR in almost all tissues – meaning once bound, they maximally activate the receptor’s transcriptional activity everywhere. Nonsteroidal SARMs are often selective agonists, behaving as full agonists in some tissues (like muscle or bone) but only partial agonists in others (like the prostate)pmc.ncbi.nlm.nih.gov. This tissue selectivity arises from differences in how the receptor-ligand complex recruits co-regulator proteins. A steroidal androgen and a nonsteroidal SARM induce distinct conformational changes in the AR’s structurepmc.ncbi.nlm.nih.gov. Consequently, the AR bound to a nonsteroidal ligand might attract coactivator proteins strongly in muscle cells but less so in prostate cells, for example, leading to high anabolic (muscle-building) activity with relatively lower stimulation of prostate growth. Steroidal hormones tend not to discriminate in this way – they “turn on” AR target genes broadly.
Receptor co-regulator interactions: The AR has surfaces (AF-2 region, etc.) where transcriptional co-regulators bind. Steroidal androgens vs. nonsteroidal androgens can alter the shape of these surfaces differentlypmc.ncbi.nlm.nih.gov. Research has shown that ligand-specific conformations modulate which co-regulators (coactivators or corepressors) are recruited. For instance, a study comparing DHT (steroidal) and a SARM (nonsteroidal aryl-propionamide S-22) found that each ligand triggered assembly of a different set of proteins at androgen-responsive genespubmed.ncbi.nlm.nih.gov. Such differences in molecular modulation mean that the downstream gene expression profile from a nonsteroidal androgen may not be identical to that from a steroid hormone, even if both bind the same receptor.
Genomic vs. non-genomic effects: Steroid hormones including androgens can have non-genomic actions – rapid signaling events outside of direct DNA regulation (for example, activating kinase pathways within minutes of binding). DHT and other steroidal androgens have documented non-genomic signaling effects (through membrane-associated AR or other pathways). Nonsteroidal androgens can also trigger rapid signals, but interestingly, they may bias these pathways differently. In the case of S-22 versus DHT, researchers observed that each activated distinct sets of kinase signaling cascades inside cellspubmed.ncbi.nlm.nih.gov. This suggests that the signaling pathway activation can diverge between steroidal vs. nonsteroidal AR ligands, contributing to their unique pharmacological profiles.
Partial agonism and antagonism: Some steroidal androgen derivatives (like certain synthetic anabolic steroids) also have partial agonist or antagonist properties in specific contexts, but a key historical observation was that the first steroidal antiandrogens (e.g. cyproterone acetate) were actually partial agonists at the AR, which limited their clinical utilitymdpi.com mdpi.com. Nonsteroidal antiandrogens (like flutamide or bicalutamide), on the other hand, were designed to be pure antagonists with no agonist activitymdpi.com. This exemplifies how a nonsteroidal structure could achieve a cleaner blockade of the receptor. Similarly, modern nonsteroidal SARMs aim to avoid undesired activation in certain tissues. In essence, the nonsteroidal molecules give researchers more control to fine-tune the mechanism of action – whether we want activation or inhibition, full blast or partial – whereas steroidal androgens tend to exert broad, non-discriminatory activation of AR pathways.

Understanding these mechanistic nuances was crucial in the historical development of SARMs. It became clear that by changing the chemistry of the ligand, one could change the biology of the response. This insight directly informed the next generation of androgen therapeutics.

Clinical Implications of Steroidal vs. Nonsteroidal Androgens

The differences between steroidal and nonsteroidal androgens are not just academic – they translate into real-world clinical implications for therapy and drug development. Historically and today, these distinctions impact how androgens are used in medicine:

Benefits and limitations of steroidal androgens: Steroidal androgens (like testosterone and its analogs) have well-known anabolic benefits – they can restore libido, increase muscle mass, boost bone density, and more. Clinically, testosterone replacement therapy has been a cornerstone for treating hypogonadism and certain wasting conditions. However, the limitations of steroidal androgens are equally well known: poor oral availability (requiring injections or liver-taxing modifications), lack of tissue selectivity, and a spectrum of side effects. For example, anabolic steroid use leads to androgenic side effects such as prostate enlargement, acne, hair loss, and virilization in women. Because steroidal androgens can convert to estrogen, there’s also risk of gynecomastia and fluid retention. These side effects place limits on clinical use of high-dose testosterone or anabolic steroidspubmed.ncbi.nlm.nih.gov. In prostate cancer or benign prostate hyperplasia, the androgenic stimulation by steroidal androgens is actually detrimental – hence those conditions are treated by suppressing or blocking AR.
Therapeutic potential of nonsteroidal androgens: Nonsteroidal AR ligands were developed to harness anabolic benefits without the undesired effects of steroid hormones. Nonsteroidal SARMs in particular were designed to stimulate muscle and bone growth while sparing other tissues. For instance, nonsteroidal SARMs do not undergo 5α-reduction, so they avoid the extreme amplification of androgenic activity in the prostatepmc.ncbi.nlm.nih.gov. This means they inherently pose less risk for prostate-related side effects; indeed, some SARMs increase muscle size with minimal prostate growth in animal modelspubmed.ncbi.nlm.nih.gov. Additionally, lacking aromatization, they usually won’t raise estrogen levels – avoiding estrogen-driven side effects (though this also means careful monitoring of bone health might be needed). Clinically, this tissue selectivity is highly desirable. It points to SARMs as potential treatments for muscle wasting (in aging, cancer cachexia, chronic illness) with fewer androgenic complications. Nonsteroidal antiandrogens, on the other hand, provided huge clinical advances in treating prostate cancer: drugs like bicalutamide could block the AR in tumor cells without the off-target effects that steroid-based drugs like cyproterone acetate had (e.g. progestational activity, partial agonism)mdpi.com mdpi.com. In summary, nonsteroidal androgens and antiandrogens tend to offer cleaner pharmacological profiles – they can be more targeted in action, oral in administration, and have a lower incidence of hormone-related side effects.
Real-world distinctions: One practical example of the steroidal vs. nonsteroidal difference is in contraception and therapy: High-dose steroidal androgens were explored as male contraceptives (using negative feedback on the pituitary), but they often required large doses that caused systemic side effects. A nonsteroidal SARM, in theory, could be a male contraceptive by selectively suppressing gonadal axis without affecting muscle mass – a concept under investigation. In female medicine, steroidal androgens are sometimes used off-label for certain conditions, but cause virilizing side effects; a nonsteroidal selective androgen could provide therapeutic benefit (e.g. in postmenopausal sexual dysfunction or osteoporosis) with better tolerability. Additionally, in the realm of performance enhancement, traditional anabolic steroids are well-known but dangerous; the emergence of nonsteroidal SARMs on the gray market (though not approved supplements) reflects the perception that they have fewer limitations than anabolic steroidsuspharmacist.com pubmed.ncbi.nlm.nih.gov. Athletes abused SARMs in hopes of anabolic gains with less androgenic risk (though research is ongoing on long-term safety). From a clinical standpoint, while steroidal androgens remain essential hormones in therapy, the nonsteroidal androgens are at the forefront of developing safer androgen therapies.

Historical Significance for Modern SARMs Development

Looking back at the historical development of SARMs, the contrast between steroidal and nonsteroidal androgens has been a driving force in drug discovery. Key historical insights include:

Researchers in the mid-20th century recognized that simply modifying the testosterone molecule (producing steroidal SARMs) had intrinsic limitations – many such analogs were tested from the 1940s onward with only modest successpmc.ncbi.nlm.nih.gov. The real breakthrough came in the 1990s with the modern era of nonsteroidal SARMspmc.ncbi.nlm.nih.gov. Pioneering work by pharmaceutical teams (at Ligand Pharmaceuticals and the University of Tennessee) showed that nonsteroidal structures could act as potent AR agonists with tissue selectivitypmc.ncbi.nlm.nih.gov. For example, Ligand’s scientists developed quinolinone derivatives that built muscle in rats while sparing the prostate, and Dalton et al. discovered that analogs of the nonsteroidal antiandrogen bicalutamide could be tweaked to become agonists instead of antagonistspmc.ncbi.nlm.nih.gov. These findings essentially flipped the script – a compound class originally meant to block AR (nonsteroidal antiandrogens) was re-engineered to activate AR in a selective way.
Design principles learned: The difference between how a steroidal vs. nonsteroidal ligand engages the androgen receptor taught scientists about receptor dynamics. For instance, it was learned that receptor binding is not one-size-fits-all – the AR’s ligand-binding pocket can accommodate diverse shapes, and the shape it adopts can dictate which genes turn on. This realization has guided the design of newer SARMs: chemists incorporate features that favor certain receptor conformations (to promote muscle gain) and avoid others (that might trigger prostate or sebaceous gland activation). The historical context of knowing steroid metabolism also guides modern SARMs – because nonsteroidal androgens do not convert to DHT, some researchers propose that we might be “overlooking the role of 5α-reductase” in old drug effectspubmed.ncbi.nlm.nih.gov. In other words, part of why SARMs are gentler on certain tissues is because they sidestep the amplifying enzymes that steroids fall prey to.
Evolution of pharmacological understanding: The journey from testosterone injections to refined nonsteroidal SARMs reflects an evolution in pharmacology – from hormone replacement to hormone receptor modulation. Early on, the discovery of the AR itself was a catalyst: once scientists knew an androgen receptor existed, they could move from using crude steroid extracts to rationally designing molecules for that target. Steroidal androgens served as the first template, but nonsteroidal modulators became the ultimate goal for achieving selectivity. This progression is a major chapter in the historical development of SARMs, demonstrating how understanding molecular mechanisms leads to better drugs.

Today, SARMs in development owe their existence to those decades of research dissecting steroidal vs. nonsteroidal effects. The differences in structure and action are not just a curiosity – they were the clues that helped scientists create a new class of drugs. As ongoing research delivers second-generation SARMs and beyond, the lessons from both steroidal hormones and nonsteroidal experiments remain fundamental.

FAQs

What are the fundamental chemical differences between steroidal and nonsteroidal androgens?
Steroidal androgens have the four-ring steroid core structure (derived from the cholesterol backbone), meaning they are all variations of the testosterone-like skeleton. Nonsteroidal androgens lack this steroid ring system entirely – instead, they come in various chemical forms (such as aromatic rings, heterocycles, etc.) designed to fit the androgen receptor without being actual steroidsen.wikipedia.org. In essence, steroidal androgens are chemically “steroids,” whereas nonsteroidal androgens are other organic compounds that can bind the AR. This structural gulf leads to differences in how they are metabolized and what other receptors they might incidentally affect.
How did the discovery of androgen receptors influence the understanding of steroidal and nonsteroidal androgen mechanisms?
Identifying the androgen receptor in the 1960s fundamentally changed our understanding. It proved that androgens work through a specific receptor proteinpubmed.ncbi.nlm.nih.gov, which meant scientists could focus on how different molecules engage that target. For steroidal androgens, it explained their potent effects and side effects as a consequence of receptor binding (and even helped uncover enzymes like 5α-reductase that create more potent metabolitespubmed.ncbi.nlm.nih.gov). For nonsteroidal compounds, knowing the AR was the key allowed researchers to intentionally design drugs that target the receptor. The discovery of AR showed that mechanisms of action could vary with different ligands – e.g. a steroid vs. a nonsteroid might induce different receptor conformations and cofactor interactionspmc.ncbi.nlm.nih.gov. In short, learning about the AR enabled the concept of selective modulators: it bridged classical endocrinology with medicinal chemistry, leading directly to the development of SARMs as we know them.

Conclusion

In the grand timeline of androgen research, the contrasts between steroidal and nonsteroidal androgens have been crucial. Steroidal androgens, the body’s own hormones and early synthetic anabolic steroids, taught us what powerful effects AR activation can have – for better and worse. Nonsteroidal androgens, emerging from a deeper understanding of the androgen receptor and molecular design, showed that it’s possible to separate anabolic benefits from undesired androgenic effects. The key distinctions lie in chemical structure, metabolism, receptor interactions, and tissue selectivity. Historically, recognizing these differences propelled the historical development of SARMs, as scientists strived to create the “perfect androgen” that could heal and strengthen without harm. Today’s investigational SARMs and related therapies stand on the shoulders of those discoveries. Steroidal vs. nonsteroidal androgens are no longer just a classification – they are a narrative of scientific progress in hormonal drug development. By appreciating their differences, pharmacologists and clinicians continue to refine how we harness androgenic signaling for modern medicine. The story of these compounds highlights an ongoing balance: leveraging the potency of hormones through the precision of chemistry.

References:

Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care. 2009;12(3):232-240pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov.

Brinkmann AO. Molecular mechanisms of androgen action – a historical perspective. Methods Mol Biol.2011;776:3-24pubmed.ncbi.nlm.nih.gov.

Narayanan R, Coss CC, et al. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate AR function through distinct genomic and nongenomic pathways. Mol Endocrinol.2008;22(11):2448-65pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov.