The Relationship Between Androgens, Their Receptors, and Diseases

Androgen Biosynthesis and Metabolism

Androgens start their production with cholesterol, converted into testosterone in the testes' Leydig cells. This is initiated as early as the sixth week of gestation, and initially doesn't depend on LH. But, as testis grows, LH from the pituitary gland skews testosterone levels. LH is modulated by the hypothalamus through gonadotropin-releasing hormone (GnRH), which testosterone negative feedbacks to inhibit.

Conversion of cholesterol to testosterone is multi-step process. It first proceeds through steroidogenic acute regulatory protein (StAR), which makes cholesterol travel to mitochondria. HP450scc here side-chains cholesterol into pregnenolone, the lowest energy androgen biosynthesis step. Then it goes on to enzymes like 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase type 3. Or testosterone, converted into DHT by 5-reductase type 2, a permanent testosterone-to-DHT conversion enzyme. It is the conversion responsible for male external genitalia such as the penis and scrotum to be differentiated. Recent research has also highlighted an alternative "backdoor" pathway for DHT production, which plays a role in fetal masculinization and certain disorders like congenital adrenal hyperplasia.

Figure 1. Androgen synthesis from cholesterol
(Source: Carbajal-García A, et al. 2020)

Androgen Receptor

AR belongs to the steroid nuclear receptor superfamily. The estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), and salt corticosteroid receptor (MR) also belong to this family. AR is located on the X chromosome and its mRNA measures around 10.6 kb in length and consists of eight exons. AR has four functional domains in its structure: NH₂-terminal domain (for transcriptional activation), DNA-binding domain (DBD) that binds particular DNA sequences, a hinge region, and ligand-binding domain (LBD). When AR is ligand-bound, it conformase and is open to binding other proteins involved in gene regulation. They include coactivators, which boost transcription, and corepressors, which stop it. AR can be very different in the structure, network of protein interactions, and binding to chromatin, causing transcriptional and drug responses to change. For instance, in androgen insensitivity syndrome (AIS), individuals may exhibit defective sexual characteristics despite normal or elevated levels of circulating androgens.

Figure 2. Functional domains of the androgen receptor
(Source: Davey RA, et al. 2016)

The functionality of the AR is influenced by the CAG and GGN repeat sequences in its N-terminal domain, with the length of the CAG repeat being highly variable among individuals. In a normal state, the length of the CAG repeat in the AR gene ranges from 9 to 39 repeats, showing regional differences within populations of the same country. There is an inverse correlation between the length of the CAG repeat and AR transcriptional activation activity; longer CAG repeats typically reduce AR activity, while shorter repeats enhance it. Abnormal expression of the CAG repeat length in the AR gene has been observed in various androgen-related conditions, including prostate cancer, metabolic syndrome, and neurological disorders.

Androgens in Females

Androgens are precursors of oestrogen and they are pumped into higher levels than women's oestrogens. Androgens can be too strong or too low and cause reproductive endocrine conditions. Dehydroepiandrosterone (DHEA) (most commonly present as DHEA sulfate), androstenedione, testosterone and dihydrotestosterone (DHT) are the women's four dominant circulating androgens. Cyclic ovulation on the ovaries means testosterone is continuously released, reaching its peak level in the luteal stage and staying there. The testosterone in premenopausal women comes from the ovaries and from the conversion of DHEA and androstenedione into testosterone in peripheral tissues, peaking in the mid-30s and 40s, then gradually falling off with age.

Figure 4. Circulating androgens in women
(Source: Giovannelli P, et al. 2018)

The two main manifestations of polycystic ovary syndrome (PCOS) are hirsutism and anovulatory infertility, although other metabolic disorders include insulin resistance, diabetes and obesity. Hyperandrogenemia clearly suggests PCOS. As we now know, a hyperandrogenic milieu in the womb can cause the epigenetic reprogramming of foetal reproductive tissue to break down and create PCOS in adults. Interestingly, when tested in consistent genetic contexts, elevated androgen levels change the methylation of four human PCOS genes: luteinising hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), insulin receptor (INSR) and DENND1A in oocytes. Additionally, excess androgens are closely linked to the development of metabolic disorders. Androgen apical hypertrophy and increased pro-inflammatory factors release from fat tissue to mediate an inoflammatory low-level inflammatory cascade. In addition, boosted androgens result in selective accumulation of visceral fat in the abdomen and an increase in subcutaneous adipocyte numbers, which increases insulin resistance, LH levels and adrenocorticotropic hormone (ACTH) and metabolic malfunction.

Breast cancer is among the most common malignant tumours that women get, and it can pose an immense health risk to the patient. We know from clinical trials of breast cancer that androgens and the AR have been linked to disease. This AR signalling network not only reveals the aggressiveness of the disease but also promises possible therapy for breast cancer. AR can effectively inhibit the proliferative effects mediated by ER. Some researchers suggest that AR's primary mechanism of action is to control ERα levels by enhancing ERβ levels. ERβ, in turn, regulates the transcription of proliferation-related genes by binding with ERα as a co-transcription factor. There is also an interaction between AR and HER2; upon activation, AR can significantly increase the expression of HER2 mRNA. Studies have shown that there is a positive feedback regulation between AR and HER2 overexpression signaling, where AR activation enhances HER2 expression, subsequently promoting extracellular signal-regulated kinase (ERK) phosphorylation, which then stimulates AR in return.