The activity of the sebaceous glands is regulated by a complex network of hormonal signals, growth factors, and neuropeptide interactions. Androgens are particularly central to this regulation, beginning with 5α-dihydrotestosterone (5α-DHT), which is produced by the type I 5α-reductase isoenzyme acting on testosterone. With a high affinity for the androgen receptor in the sebaceous glands, 5α-DHT activates this receptor and promotes sebocyte proliferation. Conversely, estrogens exert an inhibitory effect on sebaceous gland activity and sebum synthesis, acting as a counterbalance to androgenic effects.
Alongside sex hormones, certain growth factors influence sebaceous physiology. Growth hormone (GH) and IGF-I (insulin-like growth factor-I) are particularly involved, as evidenced by the increase in sebum secretion observed during adolescence, when GH and IGF-I reach their maximum plasma concentrations. IGF-I directly stimulates sebocyte lipogenesis by activating the transcription factor SREBP-1, a regulator of the genes involved in fatty acid synthesis. This activation occurs through the PI3K/Akt and MAPK/ERK signaling pathways. Correlations have been established between IGF-I levels and acne severity, as well as with plasma levels of 5α-DHT and DHEAS, highlighting the interconnection between lipid metabolism, androgens, and IGF-I signaling.
Another notable player is fibroblast growth factor receptor 2b (FGFR-2b), whose expression is regulated by androgens and which is involved in keratinocyte proliferation. In certain conditions such as nevus acneiformis, a malformation characterized by epidermal hyperplasia, activating mutations in FGFR-2b lead to sebaceous hyperactivity and to an alteration of the pilosebaceous unit. Experimental models have shown that postnatal deletion of FGFR-2b leads to complete atrophy of the sebaceous glands, confirming its structural role.
Regulation of sebaceous glands extends beyond hormones and growth factors. MicroRNAs, small noncoding sequences of about 21 nucleotides, provide an additional level of control by modulating gene expression post-transcriptionally. Some microRNAs, such as miR-574-3p targeting the nuclear receptor RXRα, can significantly increase lipid synthesis when overexpressed. Others, involved in sebaceous gland tumors, influence the NF-κB, PTEN, and TGF-β pathways, thereby affecting cell proliferation and transformation.
Finally, although the sebaceous gland is richly vascularized to meet its high demands for nutrients and lipid precursors, its innervation remains less well characterized. Nerve networks surround the hair follicle and lie in close proximity to the gland, but the direct penetration of nerve fibers into it is still under debate. However, the presence of receptors for various neuropeptides, such as CRH (corticotropin-releasing hormone), α-MSH, or β-endorphin, suggests a heightened sensitivity to neuroendocrine signals. For example, CRH released in a circadian manner by the hypothalamus modulates the secretion of ACTH and POMC-derived peptides, which can directly influence the proliferation and differentiation of sebaceous glands.
The physiology of sebaceous glands thus relies on a dynamic balance between hormonal signals, growth factors, post-transcriptional regulation, and neuropeptide responses, each contributing to the modulation of cell proliferation and sebum production.