Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use. Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833). Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980). Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception. Clinical Trial Registration: www.ClinicalTrials.gov registration NCT02367833.

Indices of Resting Metabolic Rate Accurately Reflect Energy Deficiency in Exercising Women.

Energy deficiency in exercising women can lead to physiological consequences. No gold standard exists to accurately estimate energy deficiency, but measured-to-predicted resting metabolic rate (RMR) ratio has been used to categorize women as energy deficient. The purpose of the study was to (a) evaluate the accuracy of RMR prediction methods, (b) determine the relationships with physiological consequences of energy deficiency, and (c) evaluate ratio thresholds in a cross-sectional comparison of ovulatory, amenorrheic, or subclinical menstrual disturbances in exercising women (n = 217). Dual-energy X-ray absorptiometry (DXA) and indirect calorimetry provided data on anthropometrics and energy expenditure. Harris-Benedict, DXA, and Cunningham (1980 and 1991) equations were used to estimate RMR and RMR ratio. Group differences were assessed (analysis of variance and Kruskal-Wallis tests); logistic regression and Spearman correlations related ratios with consequences of energy deficiency (i.e., low total triiodothyronine; TT3). Sensitivity and specificity calculations evaluated ratio thresholds. Amenorrheic women had lower RMR (p < .05), DXA ratio (p < .01), Cunningham1980 (p < .05) and Cunningham1991 (p < .05) ratio, and TT3 (p < .01) compared with the ovulatory group. Each prediction equation overestimated measured RMR (p < .001), but predicted (p < .001) and positively correlated with TT3 (r = .329-.453). A 0.90 ratio threshold yielded highest sensitivity for Cunningham1980 (0.90) and Harris-Benedict (0.87) methods, but a higher ratio threshold was best for DXA (0.94) and Cunningham1991 (0.92) methods to yield a sensitivity of 0.80. In conclusion, each ratio predicted and correlated with TT3, supporting the use of RMR ratio as an alternative assessment of energetic status in exercising women. However, a 0.90 ratio cutoff is not universal across RMR estimation methods.

Comparison of Female Athlete Triad Coalition and RED-S risk assessment tools.

The Female Athlete Triad Coalition (Triad Coalition) and Relative Energy Deficiency in Sport (RED-S) consensus statements each include risk assessment tools to guide athlete eligibility decisions. This study examined how these tools categorized the same set of individuals to an overall risk factor score and qualitatively compared athlete eligibility decisions resulting from each tool. Exercising women (n = 166) with complete screening/baseline datasets from multiple previously conducted studies were assessed. Data used for risk assessment included: anthropometric measurements, dual-energy x-ray absorptiometry scans, exercise and health status surveys, and two disordered eating questionnaires (Three Factor Eating Questionnaire and Eating Disorder Inventory). Individuals were scored on each tool and subsequently categorized as either fully cleared, provisionally cleared, or restricted from play. Based on the Triad Coalition tool, 25.3% of subjects were classified as fully cleared, 62.0% as provisionally cleared, and 12.7% as restricted from play. Based on the RED-S tool, 71.7% of subjects were classified as fully cleared, 18.7% as provisionally cleared, and 9.6% as restricted from play. The Triad Coalition and RED-S tools resulted in different clearance decisions (p < 0.001), with the Triad Coalition tool recommending increased surveillance of a greater number of athletes.

Geometric and "True" Densitometric Characteristics of Bones in Athletes with Stress Fracture and Menstrual Disturbances: A Systematic Review.

BACKGROUND: Stress fractures can lead to short- and long-term consequences, impacting participation in sport and general health. Recognizing which skeletal characteristics render bones susceptible to stress fracture may aid stress-fracture prevention. Menstrual disturbances among exercising women are a known risk factor for stress fracture; therefore, assessing skeletal commonalities between women with stress fractures and women with menstrual disturbances may increase our understanding of why menstrual disturbances put athletes at greater risk for stress fracture. Three-dimensional (3D) bone imaging tools provide detailed information about volumetric bone mineral density (vBMD) and bone structure that cannot be obtained using traditional two-dimensional (2D) techniques. OBJECTIVES: This systematic review serves to: (1) evaluate the current literature available on vBMD, bone geometry, and bone structure in exercising women with menstrual disturbances and exercising women with stress fractures, and (2) assess the common skeletal characteristics between both conditions. Our aim is to reveal bone properties beyond 2D areal BMD that may indicate increased susceptibility to stress fracture among exercising women with menstrual disturbances. SEARCH METHODS: A search of the PubMed/Medline database was completed in May 2018. ELIGIBILITY CRITERIA: Eligible articles included those that reported vBMD, bone geometry, or bone structure obtained from 3D imaging techniques or estimated from 2D imaging techniques. Only studies conducted in premenopausal exercising women and girls who had a stress fracture, a menstrual disturbance, or both were included. RESULTS: Twenty-four articles met the inclusion criteria. Bone area and cortical thickness at the tibia were identified as altered both in women with menstrual disturbances and in women with stress fractures; however, there was inconsistency in the results observed for all bone parameters. The majority of skeletal parameters of the lower extremities were not significantly different between exercising women with and without stress fractures and between those with and without menstrual disturbances. DISCUSSION: Most studies were moderate or low quality based on study design, and only one article combined both conditions to explore vBMD and bone geometry in athletes with menstrual disturbances and a history of stress fracture. These findings highlight the need for more skeletal research on the intersection of these health conditions in exercising women. The lack of observed differences in skeletal parameters suggests that risk factors other than bone geometry and structure may be the primary causes of stress fracture in these women.

Energy Deficiency Suppresses Bone Turnover in Exercising Women With Menstrual Disturbances.

CONTEXT: In exercising women, energy deficiency can disrupt the balance of bone formation and resorption, resulting in bone loss and an altered rate of bone turnover, which may influence future bone mineral density and fracture risk. OBJECTIVE: To assess the effects of energy status and estrogen status on bone turnover. DESIGN: Cross-sectional. SETTING: The Women's Health and Exercise Laboratory at Pennsylvania State University. PARTICIPANTS: Exercising women (n = 109) operationally defined as energy deficient or replete based on total triiodothyronine concentration and as estrogen deficient or replete based on menstrual cycle history and reproductive hormone metabolites. MAIN OUTCOME MEASURES: Bone formation index [procollagen type I N-terminal propeptide (P1NP) concentration corrected for average P1NP concentration in healthy reference group, i.e., [P1NP]i/median [P1NP]ref], bone resorption index [serum C-terminal telopeptide (sCTx) concentration corrected for average sCTx concentration in healthy reference group, i.e., [sCTx]i/median [sCTx]ref], bone balance (ratio of bone formation index to bone resorption index to indicate which process predominates), and bone turnover rate (collective magnitude of bone formation index and bone resorption index to indicate overall amount of bone turnover). RESULTS: The combination of energy and estrogen deficiency resulted in less bone formation and a lower rate of bone turnover compared with women who were estrogen deficient but energy replete. Regardless of estrogen status, energy deficiency was associated with decreased bone resorption as well. No main effects of estrogen status were observed. CONCLUSIONS: The results highlight the critical role that adequate energy plays in the regulation of bone turnover, especially bone formation, in exercising women with menstrual disturbances.

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 REVIEW: This review provides an update on the primary clinical sequelae of the Female Athlete Triad. RECENT FINDINGS: Scientific 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. The 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.

Food Versus Pharmacy: Assessment of Nutritional and Pharmacological Strategies to Improve Bone Health in Energy-Deficient Exercising Women.

PURPOSE OF REVIEW: The review aims to summarize our current knowledge surrounding treatment strategies aimed at recovery of bone mass in energy-deficient women suffering from the Female Athlete Triad. RECENT FINDINGS: The independent and interactive contributions of energy status versus estrogen status on bone density, geometry, and strength have recently been reported, highlighting the importance of addressing both energy and estrogen in treatment strategies for bone health. This is supported by reports that have identified energy-related features (low body weight and BMI) and estrogen-related features (late age of menarche, oligo/amenorrhea) to be significant risk factors for low bone mineral density and bone stress injury in female athletes and exercising women. Nutritional therapy is the recommended first line of treatment to recover bone mass in energy-deficient female athletes and exercising women. If nutritional therapy fails after 12 months or if fractures or significant worsening in BMD occurs, pharmacological therapy may be considered in the form of transdermal estradiol with cyclic oral progestin (not COC).

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.

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.

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

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.