Emily A. Southmayd

A summary of the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health.

Bone growth, development, and remodeling are modulated by numerous circulating hormones. Throughout the lifespan, the extent to which each of the hormones impacts bone differs. Understanding the independent and combined impact of these hormones on controlling bone remodeling allows for the development of more informed decision making regarding pharmacology, specifically the use of hormonal medication, at all ages. Endocrine control of bone health in women is largely dictated by the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis and the hypothalamic-pituitary-ovarian (HPO) axis. Growth hormone, secreted from the pituitary gland, stimulates cells in almost every tissue to secrete IGF-1, although the majority of circulating IGF-1 is produced hepatically. Indeed, systemic IGF-1 concentrations have been found to be correlated with bone mineral density (BMD) in both pre- and post-menopausal women and is often used as a marker of bone formation. Sex steroids produced by the ovaries, namely estradiol, mediate bone resorption through binding to estrogen receptors on osteoclasts and osteoblasts. Specifically, by increasing osteoclast apoptosis and decreasing osteoblast apoptosis, adequate estrogen levels prevent excessive bone resorption, which helps to explain the rapid decline in bone mass that occurs with the menopausal decrease in estrogen production. Though there are documented correlations between endogenous estrogen concentrations and GH/IGF-1 dynamics, this relationship changes across the lifespan as sex-steroid dynamics fluctuate and, possibly, as tissue responsiveness to GH stimulation decreases. Aside from the known role of endogenous sex steroids on bone health, the impact of exogenous estrogen administration is of interest, as exogenous formulations further modulate GH and IGF-1 production. However, the effect and extent of GH and IGF-1 modulation seems to be largely dependent on age at administration and route of administration. Specifically, premenopausal women using combined oral contraceptive therapy (COC), post-menopausal women taking oral hormone therapy (HT), and both pre- and post-menopausal women using a transdermal form of estrogen therapy (COC or HT) demonstrate disparate GH/IGF-1 responses to exogenous estrogen. This review serves to summarize what is currently known regarding the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health.

The physiology of functional hypothalamic amenorrhea associated with energy deficiency in exercising women and in women with anorexia nervosa.

Abstract An energy deficiency is the result of inadequate energy intake relative to high energy expenditure. Often observed with the development of an energy deficiency is a high drive for thinness, dietary restraint, and weight and shape concerns in association with eating behaviors. At a basic physiologic level, a chronic energy deficiency promotes compensatory mechanisms to conserve fuel for vital physiologic function. Alterations have been documented in resting energy expenditure (REE) and metabolic hormones. Observed metabolic alterations include nutritionally acquired growth hormone resistance and reduced insulin-like growth factor-1 (IGF-1) concentrations; hypercortisolemia; increased ghrelin, peptide YY, and adiponectin; and decreased leptin, triiodothyronine, and kisspeptin. The cumulative effect of the energetic and metabolic alterations is a suppression of the hypothalamic-pituitary-ovarian axis. Gonadotropin releasing hormone secretion is decreased with consequent suppression of luteinizing hormone and follicle stimulating hormone release. Alterations in hypothalamic-pituitary secretion alters the production of estrogen and progesterone resulting in subclinical or clinical menstrual dysfunction.

Current and past menstrual status is an important determinant of femoral neck geometry in exercising women

UNLABELLED Menstrual status, both past and current, has been established as an important determinant of bone mineral density (BMD) in young exercising women. However, little is known regarding the association between the cumulative effect of menstrual status and indices of bone health beyond BMD, such as bone geometry and estimated bone strength. PURPOSE This study explores the association between cumulative menstrual status and indices of bone health assessed using dual-energy x-ray absorptiometry (DXA), including femoral neck geometry and strength and areal BMD (aBMD), in exercising women. METHODS 101 exercising women (22.0±0.4years, BMI 21.0±0.2kg/m(2), 520±40min/week of self-reported exercise) participated in this cross-sectional study. Women were divided into three groups as follows based on their self-reported current and past menstrual status: 1) current and past regular menstrual cycles (C+P-R) (n=23), 2) current and past irregular menstrual cycles (C+P-IR) (n=56), 3) and current or past irregular cycles (C/P-RIR) (n=22). Current menstrual status was confirmed using daily urinary metabolites of reproductive hormones. DXA was used to assess estimates of femoral neck geometry and strength from hip strength analysis (HSA), aBMD, and body composition. Cross-sectional moment of inertia (CSMI), cross-sectional area (CSA), strength index (SI), diameter, and section modulus (Z) were calculated at the femoral neck. Low CSMI, CSA, SI, diameter, and Z were operationally defined as values below the median. Areal BMD (g/cm(2)) and Z-scores were determined at the lumbar spine, femoral neck, and total hip. Low BMD was defined as a Z-score<-1.0. Chi-square tests and multivariable logistic regression were performed to compare the prevalence and determine the odds, respectively, of low bone geometry, strength, and aBMD among groups. RESULTS Cumulative menstrual status was identified as a significant predictor of low femoral neck CSMI (p=0.005), CSA (p≤0.024), and diameter (p=0.042) after controlling for confounding variables. C+P-IR or C/P-RIR were four to eight times more likely to exhibit low femoral neck CSMI or CSA when compared with C+P-R. Lumbar spine aBMD and Z-score were lower in C+P-IR when compared with C+P-R (p≤0.003). A significant association between menstrual group and low aBMD was observed at the lumbar spine (p=0.006) but not at the femoral neck or total hip (p>0.05). However, after controlling for confounding variables, cumulative menstrual status was not a significant predictor of low aBMD. CONCLUSION In exercising women, the cumulative effect of current and past menstrual irregularity appears to be an important predictor of lower estimates of femoral neck geometry, as observed by smaller CSMI and CSA, which may serve as an another means, beyond BMD, by which menstrual irregularity compromises bone strength. As such, evaluation of both current and past menstrual status is recommended to determine potential risk for relatively small bone geometry at the femoral neck.

Low resting metabolic rate in exercise-associated amenorrhea is not due to a reduced proportion of highly active metabolic tissue compartments.

Exercising women with menstrual disturbances frequently display a low resting metabolic rate (RMR) when RMR is expressed relative to body size or lean mass. However, normalizing RMR for body size or lean mass does not account for potential differences in the size of tissue compartments with varying metabolic activities. To explore whether the apparent RMR suppression in women with exercise-associated amenorrhea is a consequence of a lower proportion of highly active metabolic tissue compartments or the result of metabolic adaptations related to energy conservation at the tissue level, RMR and metabolic tissue compartments were compared among exercising women with amenorrhea (AMEN; n = 42) and exercising women with eumenorrheic, ovulatory menstrual cycles (OV; n = 37). RMR was measured using indirect calorimetry and predicted from the size of metabolic tissue compartments as measured by dual-energy X-ray absorptiometry (DEXA). Measured RMR was lower than DEXA-predicted RMR in AMEN (1,215 ± 31 vs. 1,327 ± 18 kcal/day, P < 0.001) but not in OV (1,284 ± 24 vs. 1,252 ± 17, P = 0.16), resulting in a lower ratio of measured to DEXA-predicted RMR in AMEN (91 ± 2%) vs. OV (103 ± 2%, P < 0.001). AMEN displayed proportionally more residual mass (P < 0.001) and less adipose tissue (P = 0.003) compared with OV. A lower ratio of measured to DXA-predicted RMR was associated with lower serum total triiodothyronine (ρ = 0.38, P < 0.001) and leptin (ρ = 0.32, P = 0.004). Our findings suggest that RMR suppression in this population is not the result of a reduced size of highly active metabolic tissue compartments but is due to metabolic and endocrine adaptations at the tissue level that are indicative of energy conservation.

Iron status at opposite ends of the menstrual function spectrum

OBJECTIVES Although exercising women are at high risk of poor iron status, it is unknown how non-pathological, physiological menstrual function affects iron status. As such, this study investigates the association between menstrual function and iron status in exercising women with amenorrhea and exercising women with ovulatory, eumenorrheic menstrual cycles. DESIGN Cross-sectional analysis of iron depletion prevalence, iron status indices, exercise parameters, and diet composition. METHODS Women aged 18-35 years performing at least 2 h per week of aerobic exercise were recruited. Women with amenorrhea (AMEN) were defined by the absence of menses for at least 90 days or less than 6 menses in the past 12 months (n = 82). Women with ovulatory, eumenorrheic menstrual cycles (OvEU) were defined by the presence of ovulatory cycles of 26-35 days in length for the past 6 months (n = 109). Group differences in serum ferritin (Ft), soluble transferrin receptor (sTfR), total body iron (TBI), hemoglobin (Hb), hematocrit (Hct), iron depletion prevalence (Ft <15 μg/L), peak oxygen consumption (VO2peak), exercise minutes per week, and diet logs were assessed. RESULTS The prevalence of iron depletion was greater in OvEU when compared to AMEN (26% vs. 15%, p = 0.04). No significant differences were observed between AMEN and OvEU in Ft (30.2 ± 2.2 vs. 24.9 ± 2.6 μg/L; p = 0.62), sTfR (5.2 ± 1.4 vs. 4.9 ± 1.5 mg/L; p = 0.95), TBI (5.3 ± 2.7 vs. 4.8 ± 3.7 mg/kg; p = 0.42), Hb (13.2 ± 0.4 vs. 13.4 ± 0.6 g/dL; p = 0.80), Hct (39.5 ± 0.8% vs. 39.8 ± 4.1%; p = 0.93), or exercise parameters. AMEN consumed more vitamin C than OvEU (269 ± 180 vs. 129 ± 141 mg/day, p < 0.001), but all other dietary factors were similar between AMEN and OvEU. CONCLUSION Exercising women with ovulatory, eumenorrheic cycles are at a greater risk of iron depletion than exercising, amenorrheic women. Thus, menstrual function must be considered when screening for poor iron status in exercising women.

Current Status of the Female Athlete Triad: Update and Future Directions

Purpose of ReviewThis review provides an update on the primary clinical sequelae of the Female Athlete Triad.Recent FindingsScientific advancements have contributed to improve understanding of Triad-related conditions, including leptin’s role as a potential neuroendocrine link between energy status and reproductive function. Use of finite element analysis of HRpQCT imaging has provided a more accurate assessment of bone geometry and bone strength and may be clinically relevant. New perspectives aimed at developing and implementing a multi-disciplinary, personalized approach in the prevention and early treatment of triad-related symptoms are provided.SummaryThe Female Athlete Triad is a multi-dimensional condition that affects active women across the lifespan. Energy availability impacts reproductive function and bone with implications for health and performance. Understanding the contributions of each individual component as well as their interconnected effects is necessary for progression and expansion of the Triad literature.