Although it would make sense that cells exposed to excess testosterone or estrogen would become “resistant” and that SHBG would increase to bind available hormones, the literature does not appear to address this issue in depth.
Hormone resistance refers to a reduction or lack of target tissue response to a biologically active hormone. It may be related to an excess or lack of hormones. However, serum levels of the hormone in question are usually within normal range or increased due to a lack of normal feedback regulation. Hormone resistance can lead to a variety of disorders including (Metwalley 2021):
- Androgen insensitivity syndrome
- Familial glucocorticoid deficiency
- Insulin resistance (most common)
- Laron syndrome (growth hormone insensitivity)
- Nephrogenic diabetes insipidus (resistance to arginine vasopressin)
- Pseudohypoaldosteronism
- Pseudohypoparathyroidism
- Thyroid hormone resistance syndrome
- X linked hypophosphatemic rickets (mimics vitamin D deficiency)
Insulin resistance appears to be the most common hormone resistance disorder and is closely associated with metabolic syndrome and type 2 diabetes. In men, metabolic syndrome was strongly associated with low total testosterone and low sex hormone binding globulin (Li 2010).
Despite the regular use of androgen and estrogen therapy, associated hormone resistance is not commonly reported in the literature.
Androgen insensitivity syndrome is a rare, genetic, receptor-based disorder in which adequate testosterone is produced but the cells are unable to take it up and feminization and loss of virility occurs in males (Singh 2023). Estrogen insensitivity/resistance appears to be associated with estrogen receptor mutations as well (Li 2020).
Estrogen resistance is a recessive condition characterized by elevated estradiol and gonadotropic hormones, but with the absence of puberty and delayed bone maturation. Reproductive organs can be adversely affected in both females and males (NIH, Estrogen resistance syndrome).
Sex hormone binding globulin (SHBG) regulates the concentration of free unbound hormones in circulation as well as their delivery to target tissues. Decreased levels of SHBG, as well as single nucleotide polymorphisms related to its production and function, contribute to insulin resistance, metabolic syndrome, and type 2 diabetes. Levels of circulating SHBG have an inverse correlation with hemoglobin A1C and have been found to be low both men and women without diabetes, suggesting an early association with blood glucose dysregulation. Low SHBG has been associated with increased HOMA-IR in men and women, especially postmenopausal women (Wallace 2013). Decreased SHBG increases the bioavailability of androgens and is associated with polycystic ovary syndrome (PCOS), metabolic dysfunction-associated fatty liver disease (Qu 2020), and cardiovascular risk (Ropponen 2005).
Levels of SHBG can increase in response to oral estrogen therapy but appear to be unaffected by transdermal estrogen therapy (Ropponen 2005).
Read more in the ODX Research blog:
- SHBG measurement
- Estradiol in women and men
- Testosterone in men and women
- Insulin resistance
Note that hormone therapy resistance is different than hormone resistance and refers to cancer cells that become resistant to hormonal therapy treatments.
References
Li, Chaoyang et al. “Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men.” Diabetes care vol. 33,7 (2010): 1618-24. doi:10.2337/dc09-1788
Li, Yin et al. “ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile.” Endocrinology vol. 161,6 (2020): bqaa050. doi:10.1210/endocr/bqaa050
Metwalley, Kotb, and Hekma Farghaly. “Hormone resistance in children: what primary care physicians need to know.” Acta bio-medica : Atenei Parmensis vol. 92,4 e2021255. 2 Sep. 2021, doi:10.23750/abm.v92i4.11613 This work is licensed under a Creative Commons Attribution 4.0 International License
NIH. Estrogen resistance syndrome. https://www.ncbi.nlm.nih.gov/gtr/conditions/C3809250/
Ropponen, A et al. “Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.” The Journal of clinical endocrinology and metabolism vol. 90,6 (2005): 3431-4. doi:10.1210/jc.2005-0352
Qu, Xianqin, and Richard Donnelly. “Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome.” International journal of molecular sciences vol. 21,21 8191. 1 Nov. 2020, doi:10.3390/ijms21218191
Singh, Shikha. and Stella Ilyayeva. “Androgen Insensitivity Syndrome.” StatPearls, StatPearls Publishing, 28 February 2023.
Wallace, Ian R et al. “Sex hormone binding globulin and insulin resistance.” Clinical endocrinology vol. 78,3 (2013): 321-9. doi:10.1111/cen.12086