Does reproductive hormone status affect bone health
26 August 2022
Osteoporosis is a common disease globally, characterized by decreased bone mineral density and an increased risk of fracture. It is a major cause of morbidity and mortality, especially in post-menopausal women. In the U.S., an estimated 500,000 fractures occur each year (70% of which are hip fractures), and approximately 1.5 million Americans are currently affected by osteoporosis. Despite its high prevalence, osteoporosis remains largely under-diagnosed and under-treated worldwide. It is thought to affect up to 75% of post-menopausal women in the U.S. Osteoporosis is caused by a combination of factors, including age, gender, genetics, body composition, and hormone status.
The first step towards treating osteoporosis is identifying those at risk of the disease. Studies have shown that there is an association between osteoporosis and low circulating levels of estrogen, which is produced by the ovaries in women and by the adrenal glands in men. Therefore, the term ‘reproductive hormone’ has been coined to define the group of hormones produced by the gonads (i.e., ovaries in women and testes in men) and by the adrenal glands, which influence bone health. This group of hormones includes estrogen, progesterone, and testosterone. The latter is also known as androgen, due to its significant role in masculinization.
As previously mentioned, low levels of estrogen are associated with increased risk of osteoporosis. Progesterone has a similar effect on bone health to that of estrogen, although its exact mechanism of action is not well understood. Progestogenes are synthetized from pre-menopausal progesterone, and in men, they have been shown to suppress osteoclast activity and to increase osteoblast function and bone mineral density. However, these effects are generally minimal and their clinical significance is questioned. Some investigators have speculated that progesterone might protect the bones from osteoporosis by increasing insulin-like growth factor-1 (IGF-1) levels, which promotes osteoblast differentiation and activity. Tests in animals have shown that progesterone can increase IGF-1 by up to 18%, further supporting its potential to positively affect bone health.
Testosterone is the primary androgen in men and is also produced by the adrenal glands. It is a potent anabolic steroid and has a crucial role in promoting linear growth and bone mineralization in children and adolescents. It also has a role in maintaining muscle mass and strength in the adult male. Like estrogen and progesterone, testosterone has been shown in numerous animal studies to have a positive effect on bone health. In fact, the anabolic effects of testosterone on bone might be even greater than those of estrogen and progesterone combined, as it has been shown to increase osteoblast function, activity, and proliferation. In support of this, clinical studies have shown that testosterone treatment increases bone mineral density and osteoblast activity in men with low bone mass due to low levels of estrogen, further supporting its positive effect on bone health.
Based on the data collected so far, it seems plausible to hypothesize that testosterone and estrogen work in concert to positively affect bone health, with the latter serving as a coupling agent for the former. This hypothesis is further supported by studies that have shown that estrogen treatment significantly increased the expression of aromatase (CYP19A1), the enzyme responsible for the synthesis of estrogen, in osteoblasts and osteoclasts. Aromatase converts androgen to estrogen and is therefore necessary for both male and female reproduction. Interestingly, aromatase deficiency in mice has been shown to lead to osteoporosis, further supporting the theory that an optimal level of estrogen is important for maintaining healthy bones. These studies demonstrate the complexity of the interplay between the endocrine and exocrine systems in regulating bone health. The exocrine (i.e., secretory) system consists of hormones (e.g., growth hormone, prolactin, and cortisol) produced by the endocrine glands (e.g., pituitary, pancreas, and adrenal glands) and functions in maintaining homeostasis. The endocrine (i.e., signaling) system consists of hormones (e.g., insulin, growth hormone, and estrogen) that are produced by the cells of the body and help regulate functions such as growth and metabolism. Importantly, it appears that the interplay between the endocrine and exocrine systems influences bone health in both a positive and negative direction. For example, while cortisol (a glucocorticoid) has been shown to have a major negative effect on bone health, its deficiency has also been shown to lead to high bone mass in men and in women due to positive feedback caused by elevated levels of estrogen and insulin, respectively.
Reproductive Hormone Therapy and Post-menopausal Osteoporosis
Hormone replacement therapy (HRT) is a medical treatment that consists of the replacement of hormones that are abnormally low or absent in the body. HRT has long been used to treat menopausal symptoms such as hot flashes, night sweats, and sleep apnea. More recently, it has been recommended for the prevention and treatment of osteoporosis and menopausal symptoms associated with osteoporosis. As mentioned, estrogen has a positive effect on bone health, while progesterone and testosterone have been shown to have a protective effect. As a result, hormone replacement therapy (HRT) is commonly used to treat menopausal symptoms associated with osteoporosis. There are two main types of HRT, namely, combined therapy and non-combined therapy. In combined therapy, estrogen is given in combination with progesterone or testosterone. The latter is used to treat men suffering from hypogonadism, defined as the clinical disorder of gonadal dysfunction, which results in low testosterone levels. While non-combined HRT allows for the use of estrogen or progesterone alone in menopausal women, who are either unable or unwilling to produce testosterone, it is still considered an effective treatment for postmenopausal osteoporosis due to its positive effect on bone health.
Does Reproductive Hormone Status Affect Bone Health?
To answer this question, we first need to understand the physiology of bone health. As previously mentioned, there is a delicate balance between osteoblasts, which promote bone mineralization, and osteoclasts, which promote bone resorption. Osteoblasts are stimulated to promote bone mineralization by growth factors (e.g., bone morphogenetic protein 2) and hormones (e.g., estrogen). On the other hand, osteoclasts are stimulated to promote bone resorption by bone matrix proteins (e.g., osteopontin) and certain cytokines (e.g., IL-1 and TNF-α). In response to this, osteoblasts secrete osteoprotegrin (OPG), which inhibits the differentiation and activity of osteoclasts. As a result, optimal bone health results from a balance between bone formation and bone resorption, with the former being favored over the latter. Interestingly, while the hormone estrogen promotes the formation of new bone and inhibits osteoclast activity, it also appears to increase the expression of RANK, the receptor for osteoprotegrin (OPG). There is also some evidence that estrogen might have a direct effect on osteoclasts, independent of RANK. This further supports the theory that estrogen promotes both bone formation and resorption.