Reproductive Hormones and Skeletal Health in Young Women

Abstract

I n young women, low estrogen levels complicate a wide variety of diseases, including premature ovarian failure, anorexia nervosa, athletic amenorrhea, prolactinoma, hypopituitarism, and chronic kidney disease. Hypoestrogenemia may also result from therapy with GnRH agonists, glucocorticosteroids, chemotherapy, and especially aromatase inhibitors. All of these situations are associated with bone loss, because estrogen chronically suppresses bone resorption. Several mechanisms are involved: 1) estrogen increases osteoclast apoptosis; 2) by suppressing interleukins and proinflammatory cytokine expression in bone marrow cells, estrogen decreases the number of osteoclasts; 3) by inhibiting the production of receptor activator of nuclear factor-B ligand, estrogen reduces the number and activity of osteoclasts; and 4) by increasing stromal cell/osteoblast cell expression of TGF␤, estrogen inhibits osteoclast activity. Estrogen also has some positive effects on bone formation by acting as a mitogen to cells early in the osteoblast line, reducing apoptosis of osteoblasts, and increasing expression of TGF␤, bone morphogenetic proteins, and IGF-I (1).In these pathological conditions, the cause of the bone loss is frequently multifactorial. For example, women with anorexia nervosa also have low IGF levels. Nonspecific factors such as poor diet, reduced exercise, or chronic inflammation may further increase bone resorption.Low estrogen levels are also seen in healthy young women who are using depo-medroxyprogesterone acetate (DMPA) for contraception. Bone loss is a side effect of this medication (2). The bone mineral density (BMD) decreases at a more rapid rate during the first years of therapy and then continues to decrease at a slower rate (3). After 5 yr, the loss is about 6% (0.5 SD). The DMPA effects are worse in teenagers; combined results from four prospective studies found an average loss of spine BMD of 3.1% over 2 yr in DMPA users compared with a gain of 7.2% in untreated controls (4). A cross-sectional study in this issue by Walsh and colleagues (5) focused on the age of starting DMPA. One group aged 18 -25 started DMPA before age 20, and another group aged 35-45 started after age 34. Each group had matched controls. Importantly, the average use was 37 months in both groups. This avoids the confounding between age and duration of use, which is encountered in other studies. The BMD was significantly lower than controls when DMPA was started in teenagers but not when it was started after age 34. Estrogen levels were lower in the DMPA users than the non-hormone users and were also lower in the younger women than in the older women. The authors concluded that estrogen levels mediated the effect of DMPA on bone markers because adding DMPA to a regression model reduced the correlation between markers and estrogen. These correlations were not very strong (r ϭ Ϫ0.17 between N-telopeptide and estradiol-treated), so this is a tenuous conclusion, but it is bolstered by the findings from two other studies that adding estrogen...

Associations between prenatal serum levels of leptin, IGF-I, and estradiol and adolescent mothers’ height gain during and after pregnancy

“…This is consistent with the results of Scholl et al, who reported that higher concentrations of leptin during the third trimester of pregnancy were correlated with a greater increase in knee height [9]. In contrast, high estradiol concentrations were associated with a lower increase in height [46]. Our univariate linear model did not show differences in height increase between those who breastfed and those who did not.…”

“…As demonstrated in our study, pregnant adolescents could still grow, but probably to a lesser degree. Growth plates close approximately a decade after a teenager reaches her maximum height, meaning that a pregnant adolescent could still have time to grow [46]. We believe that this was the case in our participants, especially those who showed high concentrations of leptin.…”

The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis

“…These studies report conflicting results ( Bancroft et al ., 1991b ; Schaffir, 2006 ; Graham et al ., 2007 ; Greco et al ., 2007 ; Strufaldi et al ., 2010 ; Caruso et al ., 2011 ; Battaglia et al ., 2012 ; Elaut et al ., 2012 ; Pastor et al ., 2013 ). Although estrogens have been clearly identified as key hormones for maintaining bone mass ( Ott et al ., 2001 ; Riggs et al , 2002 ; Ott, 2008 ), androgens are also important regulators of skeletal growth and maturation ( Martel et al ., 1998 ; Riggs et al , 2002 ; Hartard et al ., 2006 ). Data on the effect of androgens in women are scarce but T may exert an effect on protein synthesis and increase muscle mass ( Gower and Nyman, 2000 ; Ružić et al ., 2003 ).…”

Bisphosphonates and Bone Turnover in Premenopausal Women Receiving Adjuvant Chemotherapy

“…Estrogens also stimulate bone formation by reducing apoptosis of osteoblast cell lines and increasing the secretion of transforming growth factor-beta, bone morphogenetic proteins, and insulin-like growth factor-1. 10,11 Conversely, estrogen deprivation after chemotherapy-induced ovarian atrophy leads to a wave of new remodeling sites by upregulation of T cells, osteoblasts, and stromal cells to produce a surge of cytokines such as interleukin-1, interleukin-6, tumor necrosis factoralpha, and RANK-L, all of which leads to enhanced osteoclast activity, the net effect of which is to tip the balance of bone turnover towards resorption. Declining estrogen stimulation in the osteoblast seems to induce estrogen receptor-alpha binding to transcriptional enhancers of Fas-ligand which upregulate the Fas-ligand gene, apparently increasing osteoclast apoptosis through a paracrine mechanism.…”