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Review
. 2021 Mar 18:9:630503.
doi: 10.3389/fcell.2021.630503. eCollection 2021.

Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers

Rachel Bleach  1 , Mark Sherlock  2 , Michael W O'Reilly  2 , Marie McIlroy  1
Affiliations
Review

Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers

Rachel Bleach et al. Front Cell Dev Biol. .

Abstract

To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.

Keywords: IGF; cancer; endocrine; metabolism; sex steroids.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
During the female lifespan sex steroid levels impact the pulsatile secretion of GH. In the premenopausal state high E2 reduces disorderliness of GH secretion. Reduction in E2 due to ovarian shutdown during menopause accompanies increases in GH pulsatile disorderliness. Created with BioRender.com.
FIGURE 2
FIGURE 2
Fasting reduces levels of IGF-1 in both genders but causes opposing effects on pulsatile GH secretion. Female GH levels become constrained in contrast to greater disorderliness of pulses in males. Created with BioRender.com.
FIGURE 3
FIGURE 3
Diagram showing crosstalk between the hypothalamic pituitary GH and IGF-1 axis and endocrine organs – testis in men, ovaries in woman and adipose tissue and adrenal gland in both sexes. All these tissue express the GHR and IGF1R and are also involved in the production of estrogens and androgens. GH, IGF and sex steroid autocrine and paracrine signalling can influence the development of endocrine-related cancers such as breast and prostate. Created with BioRender.com.
FIGURE 4
FIGURE 4
Diagram showing intracellular crosstalk between sex steroid receptors and IGF pathways in breast and prostate cancer. This illustrates the convergence of genomic and non-genomic signalling as mediators of transcriptomic gene expression in endocrine-related cancers. Created with BioRender.com.
See this image and copyright information in PMC

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