Somatotropin, estrogen, and testosterone: how genetics relates to hormones

Hormonal regulation involves many interconnected processes: hormone synthesis, transport, bioavailability, interaction with receptors, and metabolism. Genetic differences may be linked to different parts of this system.

Unlike a blood test, a DNA test does not measure how much of a hormone is circulating in the blood at a given moment. It provides a different type of information — about inherited differences linked to particular hormonal phenotypes and the mechanisms that regulate them. Somatotropin, estrogen, and testosterone have different biology and genetic architecture, so a genetic result for each of these areas needs to be interpreted with attention to exactly what is being assessed.

For more on how hormones relate to weight, energy, and mood, see the article “Weight, energy, mood, and your DNA: how hormones relate to genetics”.

A hormone level is only part of the hormonal system

Hormone synthesis is only one stage of hormonal regulation. After secretion, a hormone enters the blood, may bind to transport proteins, reaches target tissues, interacts with receptors, and triggers intracellular processes. After it is converted, inactivation and clearance follow. Genetic variants may be associated with different stages of this regulation — synthesis, transport, receptor interaction, and metabolism (Campbell & Jialal, StatPearls, 2022). Let us look at how this genetic influence is studied.

Every measurable hormonal parameter — for example, the concentration of testosterone or insulin-like growth factor 1 (IGF-1) in the blood — is a quantitative trait, or phenotype. For such phenotypes, large genome-wide association studies are carried out (GWAS), where a substantial part of the genetic variability is polygenic. This means that the value of the parameter is influenced by a large number of variants with small effects (Sinnott-Armstrong et al., eLife, 2021).

A genetic association with a hormonal parameter does not mean that a particular variant determines its actual level in the blood. It shows a statistical link between a genetic difference and a certain phenotype in the population studied — a link that is not in itself proof of causation, only a correlation.

Somatotropin and genetics: why the whole GH–IGF-1 axis matters

Somatotropin, or growth hormone (GH), does not work in isolation. First, the hypothalamus releases somatoliberin, which stimulates the release of the hormone by the pituitary gland, and part of its [growth hormone] effects is mediated through insulin-like growth factor 1 (IGF-1). Growth hormone secretion is pulsatile and depends on age, sleep, physiological state, and other factors, so a single GH measurement does not describe the entire activity of the somatotropic axis (Cappola et al., J. Clin. Endocrinol. Metab., 2023).

In a study of 150,119 whole genomes from the UK Biobank, a rare variant in the promoter region of the GHRH (growth hormone releasing hormone) gene was associated with both shorter height and lower IGF-1 levels (Halldorsson et al., Nature, 2022).

This example does not show that a single variant explains the somatotropic system; rather, it indicates that genetic differences can affect different parts of the same biological pathway. At the same time, IGF-1 also has a polygenic architecture: large GWAS reveal many genetic associations alongside biologically relevant regions (Sinnott-Armstrong et al., eLife, 2021).

Testosterone: total level, SHBG, and bioavailability are not the same thing

Total testosterone concentration is only one of the three parameters needed to describe how testosterone is regulated in the body. In the blood, the hormone is partly bound to transport proteins — in particular sex hormone-binding globulin (SHBG) — and partly remains free and bioavailable to tissues. So, besides total testosterone, two more parameters matter — SHBG itself and bioavailable testosterone: they are related but not interchangeable.

In a large analysis of 425,097 UK Biobank participants, researchers identified 2,571 significant associations for testosterone and related hormonal traits. The genetic effects on testosterone levels differed between men and women, which highlights the importance of sex when analysing these phenotypes (Ruth et al., Nat. Med., 2020).

Some of these sex differences are linked to the SHBG (sex hormone binding globulin) gene, which encodes the protein that carries androgens and estrogens in the blood. Variants in this gene and in other regions of the genome may be associated with differences in SHBG and in total or bioavailable testosterone. A UK Biobank biomarker study also showed that the genetic effects for testosterone had pronounced sex differences, whereas for most other biomarkers they largely overlapped (Flynn et al., Eur. J. Hum. Genet., 2021).

Estrogens: different hormones mean different genetic phenotypes

Estrogen is not a single universal parameter but a group of hormones. Estrogens include several compounds, and their concentrations and ratios change with age and physiological state. Estradiol is one of the main estrogens, but even its laboratory level cannot be interpreted as a measure of overall estrogenic activity.

Genetic studies of estradiol show associations in regions linked to different stages of steroid metabolism. A UK Biobank GWAS of 147,690 men and 163,985 women identified loci near genes involved in the synthesis and conversion of steroids, in particular CYP19A1 (cytochrome P450 family 19 subfamily A member 1), which encodes aromatase, as well as with processes involved in estradiol clearance (Schmitz et al., J. Clin. Endocrinol. Metab., 2021). The number of associations identified was considerably larger in men than in women: most loci reached genome-wide significance only in the male subsample (Schmitz et al., J. Clin. Endocrinol. Metab., 2021).

A separate study in a group of women showed that the genetic architecture of sex hormones may also depend on menopausal status (Haas et al., Endocrinology, 2022).

What a blood test measures, and what a genetic test measures

A laboratory test and a genetic test answer different questions. A blood test shows the concentration of a particular hormone at a specific moment or under specific sampling conditions. A genetic test assesses inherited variants that may be linked to that phenotype. These results are not interchangeable.

For hormones this is especially important, because their levels change with age, time of day, sleep, physiological state, medications, and other factors. For reproductive hormones, the result can also be affected by the measurement method and the biological context, so even a laboratory value needs proper interpretation (Abbara et al., Fertil. Steril., 2024; Cappola et al., J. Clin. Endocrinol. Metab., 2023).

Genetic information adds another layer of data: it helps reveal inherited differences linked to particular hormonal phenotypes and understand why, for one parameter, researchers may find associations across many regions of the genome, while for another they find stronger signals in a few biologically relevant regions.

How to read genetic data about hormones

In an Apixmed Prism genetic report, hormonal parameters should be read as an estimate of inherited predisposition linked to a specific trait, not as a laboratory value of the hormone. The meaning of a result depends on which phenotype was studied, which model was used, and how convincingly the relevant associations are supported in the scientific literature.

If a result is presented as a polygenic score, it should not be treated as a diagnostic threshold or as a direct prediction of a future hormone level. A genetic model describes a statistical position relative to a particular phenotype within the specific population and studies on which it is built.

For more on how to relate a genetic result to hormonal parameters, see the article “Hormonal imbalance and genetics: what a DNA test can tell you about hormones”.

Hormone genetics: what to take away from your result

Somatotropin, testosterone, and estrogens have different biology, but the shared conclusion is the same: no hormonal phenotype is described by a single gene or a single stage of regulation. The genetic contribution combines with age, physiological state, and other non-genetic factors.

Hormone genetics describes inherited differences linked to a specific hormonal parameter, not its current level in the blood. Such a result does not replace a blood test; it looks at the same hormonal system from another angle — through heredity rather than the current state.

 

Add genetic context to your personal health system

 

The results of a genetic test are not a diagnosis and not a substitute for a consultation with a doctor. An Apixmed Prism report provides genetic context that complements test results and helps you make decisions together with your doctor.

 

References

1. Sinnott-Armstrong, N., Naqvi, S., Rivas, M., Pritchard, J. K. (2021). GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background. eLife, 10, e58615. https://doi.org/10.7554/eLife.58615 

2. Ruth, K. S., Day, F. R., Tyrrell, J. et al. (2020). Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine, 26, 252–258. https://doi.org/10.1038/s41591-020-0751-5 

3. Halldorsson, B. V. et al. (2022). The sequences of 150,119 genomes in the UK Biobank. Nature, 607, 732–740. https://doi.org/10.1038/s41586-022-04965-x 

4. Flynn, E., Tanigawa, Y., Rodriguez, F. et al. (2021). Sex-specific genetic effects across biomarkers. European Journal of Human Genetics, 29, 154–163. https://doi.org/10.1038/s41431-020-00712-w 

5. Schmitz, D., Ek, W. E., Berggren, E. et al. (2021). Genome-wide Association Study of Estradiol Levels and the Causal Effect of Estradiol on Bone Mineral Density. Journal of Clinical Endocrinology & Metabolism, 106(11), e4471–e4486. https://doi.org/10.1210/clinem/dgab507 

6. Schmitz, D., Ek, W. E., Berggren, E. et al. (2022). Corrigendum to: Genome-wide Association Study of Estradiol Levels and the Causal Effect of Estradiol on Bone Mineral Density. Journal of Clinical Endocrinology & Metabolism, 107(3), e1336. https://academic.oup.com/jcem/article/107/3/e1336/6410701 

7. Haas, C. B., Hsu, L., Lampe, J. W., Wernli, K. J., Lindström, S. (2022). Cross-ancestry Genome-wide Association Studies of Sex Hormone Concentrations in Pre- and Postmenopausal Women. Endocrinology, 163(4), bqac020. https://doi.org/10.1210/endocr/bqac020 

8. Abbara, A., Adams, S., Phylactou, M. et al. (2024). Quantifying the variability in the assessment of reproductive hormone levels. Fertility and Sterility, 121(2), 334–345. https://doi.org/10.1016/j.fertnstert.2023.11.010 

9. Cappola, A. R., Auchus, R. J., El-Hajj Fuleihan, G. et al. (2023). Hormones and Aging: An Endocrine Society Scientific Statement. Journal of Clinical Endocrinology & Metabolism, 108(8), 1835–1874. https://doi.org/10.1210/clinem/dgad225 

10. Campbell, M., Jialal, I. (2022). Physiology, Endocrine Hormones. In: StatPearls [Internet]. StatPearls Publishing. PMID: 30860733. https://www.ncbi.nlm.nih.gov/books/NBK538498/