Hormonal therapy of breast cancer
A. R. Genazzani in Hormone Replacement Therapy and Cancer, 2020
The aromatase inhibitors prevent the production of estrogen from testosterone. Three agents are registered by the US FDA for therapy of metastatic breast cancer: the non-steroidal agents anastrozole and letrozole, and the steroidal agent exemestane. All are extremely potent and specific inhibitors, suppressing aromatization by 97%29, 99%30 and 98%31, respectively. These agents do not cause the estrogenic side-effects seen with tamoxifen (endometrial proliferation, thromboembolism), but are associated with its antiestrogenic side-effects (vaginal dryness, hot flushes, nausea)32, and these agents probably also lack the favorable estrogenic effects of the SERMs (bone mineralization, lipid metabolism), although this is still being studied.
Pathogenesis: Molecular mechanisms of osteoporosis
Peter V. Giannoudis, Thomas A. Einhorn in Surgical and Medical Treatment of Osteoporosis, 2020
Since estradiol production from the ovaries suddenly stops after menopause, very low estradiol levels are detected in serum, which are mostly produced by the peripheral aromatization of androgenic precursors in non-endocrine tissues. Aromatization is carried out by aromatase, which belongs to the cytochrome P450 enzyme family. This enzyme catalyzes the conversion of androstenedione to estrone as well as the conversion of testosterone to estradiol. Of note, apart from the ovarian granulosa cells, other tissues such as adipose tissue and bone tissue express aromatase (130). The role of the adipose tissue in the estrogen biosynthesis after menopause has been documented. A number of investigators have previously detected an association between fat mass and estradiol levels in serum in postmenopausal women. An inverse relationship between osteoporosis and body weight has also been reported (131,132). Estradiol production in the adipose tissue may contribute to the regulation of bone loss after menopause. Additionally, there is substantial evidence that aromatase and other enzymes participating in steroid metabolism are expressed by the bone cells (130). Thus, estradiol may act locally on bone cells, with a paracrine or even an autocrine manner, as observed in other tissues (133). Estrogen acts through binding at two different estrogen receptors, ERα and ERβ. Unfortunately, the levels of estrogen derived from peripheral aromatization are remarkably lower than those that are necessary for the preservation of a physiological remodeling process.
Hormonal regulation of spermatogenesis
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Estrogen has a substantial influence on male reproductive functions, interfering both in the hormonal cross talks and directly on testicular components. Evidence presents that male reproductive tissues mediate estrogen biosynthesis by aromatase and also express its receptors. Testes produce estrogen right from the fetal period and continuing throughout adulthood (40). Estrogen receptors (ERa and ERb) have been found to be present in juvenile, young as well as old-aged testis (40). Some cells, such as the Leydig cells, possess both ERa and ERb, while the seminiferous epithelial cells express only the ERb (40,41). It has been suggested that estrogen can modulate spermatogenesis acting at multiple levels of regulation. The most prominent function of estrogen is its participation in the negative feedback regulation of testosterone by acting on the pituitary gonadotropin secretion. Therefore, absence or inadequate exposure to estrogen results in disrupted hypothalamo-pituitary-testis axis balance. In view of the fact that this axis is a major determinant of the spermatogenic potential of the testis, its impairment via estrogen is likely to impose deleterious effects on spermatogenesis.
Hereditary breast and ovarian cancer: from genes to molecular targeted therapies
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Giovanni Ponti, Carmine De Angelis, Rosamaria Ponti, Linda Pongetti, Lorena Losi, Alberto Sticchi, Aldo Tomasi, Tomris Ozben
Hormone therapy aims to inhibit hormone synthesis or to suppress hormone stimulation of cancer cells. Tumors responsive to estrogen stimulation (ER + tumors) may be treated with drugs designed to inhibit estrogen production or the tumors’ ability to bind to estrogen receptors. These drugs are luteinizing hormone-releasing hormone agonists; in females, they hamper ovarian estrogen production (with subsequent amenorrhea), while in males, they inhibit testicular testosterone synthesis. Aromatase inhibitors block the aromatase enzyme. Aromatase is widely distributed in fat tissue, muscles and the liver and converts androgens into estrogens. Selective estrogen receptor modulators can act as competitive inhibitors of estrogens (e.g. tamoxifen) or can degrade estrogen receptors (e.g. fulvestrant). Because ovarian production is the main source of estrogens, pre-menopausal patients are assigned hormone therapy whilst post-menopausal patients are treated with aromatase inhibitors [28]. In addition, next-generation endocrine drugs, including oral SERDs, proteolysis-targeting chimeras (PROTACs), complete ER antagonists (CERAN) and selective estrogen receptor covalent antagonists (SERCA) are showing promising results in patients with ER + metastatic breast cancer and are under clinical investigation in the early stage setting [29].
A perspective on a precision approach to pain in cancer; moving beyond opioid therapy
Published in Disability and Rehabilitation, 2023
Philip Chang, Lauren Julia Amaral, Arash Asher, Daniel Clauw, Bronwen Jones, Patricia Thompson, Alix Sleight Warner
Aromatase inhibitors are used in the treatment of hormone-positive breast cancer, especially in post-menopausal women, as they contribute to estrogen depletion. While they are an essential component of treatment, one unfortunate side effect is the accompanying musculoskeletal symptoms commonly manifesting as pain and stiffness of the joints in the body, most often affecting the hands and feet [41]. The pathophysiology behind AIMSS is unknown although a leading theory is that a lack of estrogen leads to a pathologic process in cartilage creating arthritis-type symptoms in what appears to be a primary nociceptive process [41]. AIMSS is common amongst women, with prevalence ranging from 50–82%, and is a frequent cause of patients discontinuing their aromatase inhibitor therapy [42]. There are no concrete guidelines for its management and recent systematic reviews have found no substantial evidence for the use of any systemic therapy, even exercise [43,44]. A retrospective review of Medicare data examining the medications prescribed for side effects of aromatase inhibitors found that 55.1% of patients were prescribed opiates and 17.7% were prescribed tramadol for pain management [45].
Osteoanabolic therapy for osteoporosis in women
Published in Climacteric, 2022
Aromatase inhibitor therapy markedly reduces circulating estrogens, resulting in bone loss and increased fracture risk [63,64]. Similar to their effectiveness at preventing the relatively rapid bone loss that occurs with estrogen deficiency at menopause, anti-remodeling drugs prevent the bone loss associated with aromatase inhibitor therapy, and denosumab has been shown to reduce the fracture risk [65,66]. None of the osteoanabolic drugs has been studied in this population. PTH receptor agonists are not recommended in patients who have received radiation involving the skeleton because of potential osteosarcoma risk, but it is not known whether modern radiation oncologic techniques and protocols used in treating women with non-metastatic breast cancer are associated with a risk of osteosarcoma. By increasing bone resorption, teriparatide can release growth factors from the bone matrix that could potentially stimulate skeletal micro-metastasis. For these reasons, teriparatide and abaloparatide should be used with caution in breast cancer survivors with or at risk for skeletal metastases. The role of romosozumab in these patients is unknown.