Human chorionic gonadotropin (hCG): effects on the liver and kidneys

When the conversation turns to hormonal drugs, many people first think of the liver — because of the reputation of oral steroids. Human chorionic gonadotropin (hCG) works in a completely different way, and it has no described direct hepatotoxicity. However, the liver and kidneys are involved in its excretion, and the indirect consequences of the hormone's action can affect both organs. The editorial team examines what is known for certain and what are myths.

How the body excretes hCG

hCG is a glycoprotein made up of two subunits, alpha and beta, with a large number of carbohydrate chains. It is precisely the carbohydrates, in particular sialic acid residues, that make it one of the most "long-lived" hormones of this family: the half-life of hCG is much longer than that of luteinizing hormone and is measured not in minutes but in days.

The bulk of the hormone is broken down in tissues the same way as other proteins: the molecule is taken up by cells and split into peptides and amino acids, which are then reused. The liver and kidneys play a significant role in this process, but for them it is ordinary "routine" work, not a toxic load.

A smaller portion of hCG and its fragments is excreted in the urine. This is why a pregnancy test can be done on urine: it detects both the intact hormone and its beta subunit, as well as the so-called beta-core fragment (Stenman et al., 2006). The kidneys filter these molecules, and some appear in the urine unchanged.

Important: hCG is not a 17-alpha-alkylated steroid and is not metabolized by the cytochrome P450 system the way oral androgens are. Therefore the mechanism by which oral steroids damage the liver (cholestasis, peliosis, tumors) does not apply to it.

The liver: direct and indirect effects

In the official prescribing information for hCG products, hepatotoxicity is not among the characteristic adverse reactions. Special studies in people with liver failure have usually not been conducted, so in such patients decisions are made individually. The absence of a toxicity signal is not a guarantee, but neither is it grounds for the fear sometimes carried over from oral steroids.

The indirect effect is related to the fact that hCG stimulates the production of sex steroids. An excess of estrogens affects protein synthesis in the liver: the levels of sex hormone-binding globulin (SHBG), clotting factors, and transport proteins change. This in itself is not liver damage, but a change in its synthesis "program," and it matters for assessing the risk of thrombosis.

In women, the most important indirect risk is ovarian hyperstimulation syndrome. According to ASRM, in moderate and severe OHSS, abnormalities in liver tests — elevated transaminases and alkaline phosphatase — are not uncommon. They usually resolve along with the syndrome, but they indicate that the liver is involved in a systemic process.

In men who combine hCG with anabolic steroids, changes in liver tests are most often associated specifically with oral androgens rather than with the gonadotropin. However, in such a situation it is almost impossible to separate the contribution of each substance, which is exactly why doctors ask for full information about all the drugs.

The kidneys and water-salt balance

For the kidneys, the main issue is fluid. Androgens and estrogens, whose levels rise under the action of hCG, promote sodium and water retention. The prescribing information for hCG products therefore separately notes that in heart or kidney disease, as well as in conditions that could be aggravated by edema, the drug is used with caution.

In severe OHSS, fluid shifts from the vessels into the abdominal and pleural cavities. The volume of circulating blood decreases, the blood thickens, and the kidneys receive less blood. This can lead to reduced urine output, disturbed electrolyte balance and, in severe cases, acute kidney injury. This is precisely why the ASRM recommendations include monitoring of urine output, creatinine and electrolytes.

Men do not have a similar syndrome, but when combined with androgens a different load arises: increased blood pressure and hematocrit. Prolonged arterial hypertension is one of the main factors in kidney damage. The Endocrine Society review (Pope et al., 2014) mentions kidney damage among the consequences of anabolic drug abuse in general.

It is also worth remembering that during "cycles" some people simultaneously consume a great deal of protein and creatine and use NSAID painkillers. Each of these factors on its own is usually safe for healthy kidneys, but together with elevated pressure and dehydration it increases the load.

Who is at risk

The risk to the liver and kidneys with hCG depends on baseline health, concomitant drugs, and the context of use. The editorial team has singled out situations that require special attention.

People with a history of thrombosis stand apart. Although this is not a direct liver or kidney problem, estrogen-driven changes in the synthesis of clotting proteins and blood thickening during OHSS increase the risk of thromboembolic complications, which in turn can affect the renal and hepatic vessels.

Also at risk are those who use products of unknown origin. Contamination, incorrect concentration, or a different active substance can cause effects that will never appear in the prescribing information of a certified product.

Finally, it is worth remembering age: over the years the functional reserve of the kidneys declines, and what a young person tolerates without noticeable changes may manifest at an older age as elevated creatinine.

How organ status is monitored

During medical use of hCG, separate monitoring of the liver and kidneys is usually prescribed on the basis of indications, not for all patients. However, basic tests help catch a problem in time, especially if there are concomitant diseases or the drug is combined with other medications.

• Liver:ALT, AST, GGT, alkaline phosphatase, bilirubin, albumin.
• Kidneys:creatinine with GFR calculation, urea, electrolytes (sodium, potassium), a general urine test.
• Accompanying measures:blood pressure, body weight (to assess fluid retention), hematocrit.

These measures should be interpreted in context. For example, in people with a large muscle mass, creatinine can be higher without kidney disease, and transaminases rise after intense workouts because of muscle damage. A doctor may recommend cystatin C or a repeat test after several days of rest.

Any symptoms — a sharp drop in urine output, abdominal swelling, shortness of breath, rapid weight gain, yellowing of the skin, or dark urine — are a reason to seek medical help immediately rather than wait for scheduled tests.

Editorial conclusions

hCG has no direct hepatotoxicity characteristic of oral steroids, and it is excreted like an ordinary protein hormone — with the involvement of the liver and kidneys. For healthy organs this is not an excessive load.

The real risks are mostly indirect: fluid retention, changes in pressure and protein synthesis due to elevated sex steroids and, in women, ovarian hyperstimulation syndrome, which can involve both the kidneys and the liver.

With uncontrolled use, especially in combination with androgens, the contribution of hCG is hard to separate from other substances, so organ status should be assessed through tests and under a doctor's supervision.

We also recommend reading our articles on contraindications to hCG, its effect on the cardiovascular system, and the tests used during medical use.

References

1. European Medicines Agency. Ovitrelle (choriogonadotropin alfa): Summary of Product Characteristics. EMA.
2. Stenman UH, Tiitinen A, Alfthan H, Valmu L. The classification, functions and clinical use of different isoforms of HCG. Hum Reprod Update. 2006;12(6):769–784.
3. Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010;8:102.
4. Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016;106(7):1634–1647.
5. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
6. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.