Hepatocellular adenoma (HCA) is a rare benign liver tumor predominantly found in women of reproductive age or those taking oral contraceptives. These adenomas are subclassified into six molecular subtypes, each with different risks of malignant transformation. Men are less frequently affected, but HCA in men is associated with a higher risk of progressing to hepatocellular carcinoma (HCC).
HCC, the most common type of primary liver cancer, is a significant health concern globally, with over 900,000 new cases and 830,000 deaths annually. The majority of HCC cases (up to 90%) develop in the context of chronic liver disease, with liver cirrhosis being the main risk factor for hepatic carcinogenesis. The prevalence of underlying liver disease etiologies varies geographically, but the main causes include hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol abuse. Another critical cause in certain endemic areas is chronic exposure to aflatoxin B1.
A systematic HBV vaccination program and high rates of sustained virological response from direct-acting antivirals for HCV have led to a progressive shift in liver disease epidemiology, particularly in industrialized countries. There has been an increasing incidence of metabolic-associated liver disease, recently redefined as metabolic dysfunction associated steatotic liver disease (MASLD).
Regarding gender prevalence, HCC is more frequent in males, with a gender ratio of around 4:1. This disparity is partially due to higher rates of high-risk behaviors in men, such as alcohol abuse and injection drug use. Although these behaviors have increased among women, leading to a rise in chronic liver disease and liver tumors, the gender difference in HCC incidence remains significant. This suggests that intrinsic gender-specific variables play a role in this disparity.
The liver is highly susceptible to the endogenous activity of sexual hormones, including estrogens, progesterone, and androgens. Sexual hormone receptors are expressed in liver cells, with differences in gene expression patterns between men and women. Androgens, estrogens, and progesterone receptors are present in hepatocytes, with estrogen receptors also found in Kupffer and stellate cells, and progesterone receptors in cholangiocytes. Several liver diseases are influenced by sex-related gene expression patterns. Androgens and their nuclear receptors are particularly involved in liver tumor pathogenesis.
Clinical observations indicate that HCC develops at an earlier age in males and follows a more aggressive course, with worse overall survival compared to females. Men tend to present larger and multifocal tumors with macrovascular invasion and extrahepatic spread at diagnosis, making them less eligible for curative treatments. Additionally, men have a higher risk of early HCC recurrence after treatment.
Estrogens have a protective role, leading to similar overall survival rates in late postmenopausal women and age-adjusted men. The use of estrogen intake and oral contraceptives has been shown to influence HCC prognosis in women.
Anabolic androgenic steroids (AAS) are structurally related to testosterone and function by binding to androgen receptors. AAS are prescribed for medical conditions like male hypogonadism, aplastic anemia, and specific forms of osteoporosis, but are commonly abused for muscle-building and strength-enhancing purposes. Long-term use and abuse of AAS can lead to hepatotoxicity and increase the risk of liver tumor development.
Anabolic Androgenic Steroids and Their Effects
AAS are a group of natural and synthetic hormones sharing a chemical structure and biological effects. They have a steroid nucleus consisting of three cyclohexane rings and one cyclopentane ring. The term anabolic refers to their property of building skeletal muscle, while androgenic refers to their effect on inducing and maintaining male secondary sex characteristics.
AAS can be administered by intramuscular injection or oral ingestion. Intramuscular formulations are based on vegetable oils in which AAS are dissolved, with aromatic compounds added to increase solubility. These molecules can be chemically modified by esterification of the 17β-hydroxyl group to prolong their half-life. Orally ingested AAS are rapidly absorbed by the gastrointestinal tract and reach the liver via the portal system, where a significant portion is metabolized before entering systemic circulation. Despite chemical modifications, oral AAS bioavailability remains lower than parenteral forms.
AAS side effects are common, especially at supraphysiological dosages. These include sex-related side effects (e.g., male-pattern hair loss, hirsutism, dysphonia), endogenous testosterone suppression (e.g., testicular atrophy, oligo/azoospermia), and systemic adverse events (e.g., erythrocytosis, hypertension, left ventricular hypertrophy). Hepatotoxicity, demonstrated by mild elevations of liver enzymes, is a notable adverse effect. Severe manifestations like jaundice and acute hepatic failure are rare.
AAS have also been associated with the development of peliosis hepatis, hepatocellular adenomas, and carcinomas. Although the incidence of these conditions is not well established, it is considered low.
Androgens and Liver Carcinogenesis
Androgens are steroidal sex hormones produced by the ovaries, testes, and adrenal glands. Testosterone, the predominant androgen in adult men, plays a crucial role in sex characteristics development and reproduction. At physiological concentrations, most serum testosterone is transported by binding proteins. As a lipophilic molecule, it diffuses through cellular membranes and is bioactivated into DHT, which has a higher AR affinity than testosterone.
Androgens bind to AR, causing a conformational change and nuclear translocation of the AR-androgen complex, which then interacts with specific DNA sequences to regulate gene transcription involved in cell growth and survival. The Wnt/β-catenin pathway, enhanced by androgens, is one of the most studied in liver carcinogenesis. AR activation increases the transcription of cell cycle-related kinase regulators, leading to the deactivation of β-catenin inhibitors and promoting cell proliferation.
AR expression is higher in HCC tissue compared to normal liver tissue and is associated with disease progression. Studies have shown that AR knockout mice develop HCC later and less frequently than wild-type mice, highlighting the role of AR in hepatocellular proliferation.
Another mechanism is the androgen-independent induction of AR expression, driven by the mTOR pathway. The AKT-mTOR signaling pathway is hyperactivated in several malignancies, including HCC. The active mTOR complex 1 (mTORC1) phosphorylates AR, preventing its degradation and enhancing nuclear translocation. AR also exerts feedback control on the AKT-mTOR pathway by inducing the transcription of proteins that inhibit AKT, reducing mTORC1 formation.
Androgens and AR also enhance the oncogenic activity of chronic hepatitis, particularly HBV. Male HBV carriers have a significantly higher incidence of HCC than female carriers. The AR-androgen complex binds to the HBV core promoter region, enhancing viral transcription and replication. Similarly, HCV core proteins increase AR activity in the liver.
Gender differences are also observed in the expression of microRNAs (miRNAs), which play roles in genetic networks and have been associated with liver disease progression. For example, miR-216a is significantly upregulated in male HCC patients, enhancing early hepatocarcinogenesis through the AR pathway.
Estrogens and progesterone also influence liver cell proliferation. Estrogens have a protective effect against liver tumor development by modulating multiple signaling pathways. In contrast, progesterone induces abnormal liver cell proliferation, explaining the correlation between oral contraceptives and HCA development.
Hepatocellular Adenoma and Androgens
HCA is a rare benign liver tumor strongly associated with sex hormones. It is most commonly found in women of reproductive age, with an incidence of around 3 per 100,000 cases. The main risk factors for HCA include oral contraceptives and AAS use. Despite being benign, HCAs have a potential for malignant transformation, particularly in men.
HCAs are classified into four main subtypes based on morphological and molecular features: HHCA, b-HCA, IHCA, and UHCA. Molecular studies have identified a fifth subtype, sh-HCA, characterized by Sonic Hedgehog pathway activation. The risk of HCC transformation varies among these subtypes, with b-HCA carrying the highest risk.
Male patients are at higher risk of developing b-HCA due to increased androgen exposure. This correlation is particularly strong for b-HCA with mutations in exon 3 of the CTNNB1 gene, justifying the higher rate of malignant transformation in male patients. Consequently, surgical resection is recommended for men with HCA regardless of size or subtype.
Several studies have shown varying rates of malignant transformation in HCA cases. For instance, a study in Taiwan reported a 15% malignant transformation rate among male HCA cases, all of which were b-HCA. Another study in the United States found that 50% of male HCA cases expressed AR, with a concomitant presence of well-differentiated HCC in 15% of cases.
Oral contraceptive use is strongly linked to HCA development, with volume reduction or regression possible after discontinuation. Androgen exposure, particularly through AAS use, significantly increases the risk of HCA development. Multiple cases of AAS-related HCA have been reported, with many patients having hematologic disorders and long durations of treatment.
Hepatocellular Carcinoma and Androgens
HCC is the most common primary liver cancer, with sex hormones playing crucial roles in its development and progression. Several cases of AAS-related HCC have been documented, with patients often using AAS for medical conditions like Fanconi’s anemia. Most patients did not present with liver cirrhosis, highlighting the direct oncogenic effect of AAS.
Laboratory alterations, mainly mild to moderate elevations in liver enzymes such as serum bilirubin, AST, ALT, and GGT, were reported in almost all cases. These changes could be attributed to either the cancer itself or underlying hepatotoxicity caused by AAS. In many instances, only three cases showed elevated serum alpha-fetoprotein levels, indicating its low sensitivity in this patient cohort.
Immunohistochemical analyses have shown that β-catenin testing was performed in only three cases, revealing two strong and one weak positive results. Tumoral AR expression was tested in only three cases, with two cases showing AR overexpression. These findings suggest a complex interaction between androgens and liver cell proliferation.
Clinical Implications and Management
The management of AAS-induced HCC involves discontinuing AAS use and surgical intervention when possible. Survival data in these cases are limited, but the prognosis has significantly improved with advances in HCC treatment. The role of AR expression in prognosis remains inconclusive, with studies showing varying results across different histological grades. AR expression and activity appear to have different prognostic implications depending on the stage of HCC.
Current and Future Research
Recent studies have investigated the potential anti-cancer effects of anti-androgens, AR inhibitors, AR-degrading molecules, and selective AR modulators. Despite the failure of initial trials targeting the androgen-related pathway, new insights into the AR-androgen mechanism in liver cancer development have renewed interest in these therapeutic strategies. In vitro studies have shown promising results, but further research is needed to establish their efficacy in clinical settings.
Hepatocellular Adenoma Subtypes and Risks
HCA can be subclassified into six major molecular subgroups: HHCA, bex3HCA, bex7,8HCA, IHCA, sh-HCA, and UHCA. Each subtype presents unique molecular characteristics and varying risks of malignant transformation. For instance, b-HCA is characterized by activating mutations of the CTNNB1 gene, encoding β-catenin, and carries a high risk of transformation to HCC. This subtype is particularly prevalent in male patients due to increased androgen exposure.
Hormonal Influences on Liver Tumors
The liver is highly susceptible to the effects of endogenous sexual hormones such as estrogens, progesterone, and androgens. These hormones influence liver cell proliferation and tumor development through various receptors expressed in hepatocytes, Kupffer cells, stellate cells, and cholangiocytes. The differential expression of these receptors between men and women contributes to gender disparities in liver cancer incidence and progression.
The Role of MicroRNAs
MicroRNAs (miRNAs) are small, non-coding RNAs that play crucial roles in regulating gene expression. In the context of liver cancer, miRNAs have been linked to the progression of liver cirrhosis and HCC development. Androgens and AR pathways have been shown to influence miRNA expression, such as the upregulation of miR-216a in male HCC patients, which enhances early hepatocarcinogenesis.
Impact of Oral Contraceptives
The use of oral contraceptives (both estrogen-progestin and progestin-only) has been associated with the development of HCA. Volume reduction or regression of HCA is possible after discontinuation of oral contraceptives, while volume increase or recurrence can occur if therapy is resumed or during pregnancy. The relationship between oral contraceptives and HCA highlights the significant role of hormonal influences on liver tumor development.
Anabolic Androgenic Steroids and Hepatotoxicity
AAS use is associated with various adverse effects, including hepatotoxicity. Mild elevations in liver enzymes are common, but severe manifestations such as jaundice and acute hepatic failure are rare. The risk of developing liver tumors such as HCA and HCC is significantly increased with long-term AAS use. Management of AAS-induced liver tumors primarily involves discontinuing AAS use and following general HCA guidelines.
Conclusion
The complex relationship between anabolic androgenic steroids and liver tumors involves multiple molecular mechanisms and significant clinical implications. Understanding these interactions is crucial for developing effective prevention and treatment strategies for HCA and HCC, particularly in populations at high risk due to AAS use. Continued research and regulatory vigilance are essential to mitigate the hepatocarcinogenic risks associated with these substances.
APPENDIX 1 – Comprehensive Scheme Table on HCA and HCC
| Topic | Details | Recent Updates |
|---|---|---|
| Hepatocellular Adenoma (HCA) Prevalence | HCA is more frequent in women of reproductive age or taking oral contraceptives; rarer in men but with higher risk of malignant transformation. | Recent studies confirm higher incidence in women, with emerging data on genetic predispositions. |
| HCA Subtypes | Six molecular subtypes: HHCA, b-HCA, IHCA, UHCA, sh-HCA, b-IHCA. | New insights on the molecular subtypes, including genetic mutations and risk profiles. |
| HCA Risk Factors | Oral contraceptive use, AAS use, obesity, metabolic disorders like glycogenosis, galactosemia, tyrosinemia, and polycystic ovary syndrome. | Updated guidelines emphasize monitoring in high-risk groups, including new genetic markers. |
| Hepatocellular Carcinoma (HCC) Statistics | HCC is the most common primary liver cancer, with over 900,000 new cases and 830,000 deaths annually. | Global statistics updated with slightly higher incidence rates; advancements in treatment improving survival. |
| HCC Risk Factors | Chronic liver disease (cirrhosis), HBV, HCV, alcohol abuse, aflatoxin B1 exposure. | Emerging risk factors include non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome. |
| Sexual Dimorphism in Liver | HCC is more frequent in males (gender ratio 4:1), attributed to higher-risk behaviors and androgen-related mechanisms. | Recent research highlights genetic and hormonal contributions to gender disparity in HCC. |
| Impact of Sex Hormones on Liver | Sex hormones (estrogens, progesterone, androgens) influence liver cell proliferation and tumor development through receptor-mediated mechanisms. | Studies reveal more on the role of progesterone and estrogens in liver health and disease. |
| Anabolic Androgenic Steroids (AAS) Overview | AAS are synthetic derivatives of testosterone, used for medical conditions and abused for muscle building. | Increased reports of AAS abuse; new regulations and awareness campaigns. |
| AAS Administration Methods | Administered via intramuscular injection or oral ingestion; bioavailability varies between forms. | Advancements in AAS formulations for medical use, but abuse remains a concern. |
| AAS Side Effects | Common side effects include liver enzyme elevations, hepatotoxicity, male-pattern hair loss, hirsutism, testicular atrophy, hypertension, and dyslipidemia. | Comprehensive reviews on AAS side effects published recently, highlighting long-term health risks. |
| Androgens in Liver Carcinogenesis | Androgens and AR play roles in liver cell proliferation and oncogenesis through pathways like Wnt/β-catenin and mTOR. | Novel insights into androgen pathways and potential therapeutic targets for liver cancer. |
| HCA to HCC Transformation | HCA can transform into HCC, particularly in men with higher androgen exposure; b-HCA subtype has the highest risk. | Meta-analyses show varying transformation rates; new biomarkers identified for early detection. |
| Clinical Case Studies | Case studies show AAS use linked to HCA and HCC; patients often have hematologic disorders and long-term AAS use. | Large-scale studies confirm trends; ongoing trials on treatment efficacy and safety. |
| Recent Research and Updates | Recent studies on AR inhibitors and selective AR modulators show promising in vitro results; further research needed for clinical efficacy. | Ongoing research on AR pathway inhibitors showing potential; clinical trials underway. |
This table provides a detailed overview of the various aspects of HCA and HCC in relation to AAS, including prevalence, subtypes, risk factors, and recent research updates.
References
- Gastroenterology Insights. Anabolic Androgenic Steroids and Hepatocellular Adenoma and Carcinoma: Molecular Mechanisms and Clinical Implications. 2024.
- World Journal of Gastroenterology. Anabolic androgenic steroid-induced liver injury: An update. 2022.
- American Association for the Study of Liver Diseases (AASLD). What is THAT on your liver? 2024.
- Journal Watch. Characteristics of drug-induced liver injury from anabolic steroids. 2024.
- MDPI Diagnostics. Androgen-Induced, β-Catenin-Activated Hepatocellular Adenomatosis with Spontaneous External Rupture. 2024.
- https://www.mdpi.com/2036-7422/15/3/44
This detailed analysis incorporates comprehensive data on HCA and HCC in the context of AAS use, providing a thorough understanding for those without a medical background.
