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Understanding the female athlete: molecular mechanisms underpinning menstrual phase differences in exercise metabolism

European Journal of Applied Physiology volume 123, pages 423–450 (2023)Cite this article

Abstract

Research should equitably reflect responses in men and women. Including women in research, however, necessitates an understanding of the ovarian hormones and menstrual phase variations in both cellular and systems physiology. This review outlines recent advances in the multiplicity of ovarian hormone molecular signaling that elucidates the mechanisms for menstrual phase variability in exercise metabolism. The prominent endogenous estrogen, 17-β-estradiol (E2), molecular structure is bioactive in stabilizing plasma membranes and quenching free radicals and both E2 and progesterone (P4) promote the expression of antioxidant enzymes attenuating exercise-induced muscle damage in the late follicular (LF) and mid-luteal (ML) phases. E2 and P4 bind nuclear hormone receptors and membrane-bound receptors to regulate gene expression directly or indirectly, which importantly includes cross-regulated expression of their own receptors. Activation of membrane-bound receptors also regulates kinases causing rapid cellular responses. Careful analysis of these signaling pathways explains menstrual phase-specific differences. Namely, E2-promoted plasma glucose uptake during exercise, via GLUT4 expression and kinases, is nullified by E2-dominant suppression of gluconeogenic gene expression in LF and ML phases, ameliorated by carbohydrate ingestion. E2 signaling maximizes fat oxidation capacity in LF and ML phases, pending low-moderate exercise intensities, restricted nutrient availability, and high E2:P4 ratios. P4 increases protein catabolism during the luteal phase by indeterminate mechanisms. Satellite cell function supported by E2-targeted gene expression is countered by P4, explaining greater muscle strengthening from follicular phase-based training. In totality, this integrative review provides causative effects, supported by meta-analyses for quantitative actuality, highlighting research opportunities and evidence-based relevance for female athletes.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

Akt:

Protein kinase B

AMPK:

5′AMP-activated protein kinase

AP-1:

Activator protein 1

BCOAD:

Branched-chain 2-oxo-acid dehydrogenase

cAMP:

Cyclic-AMP

CD36:

Fatty acid translocase

CEBPA:

CCAAT/enhancer-binding protein alpha

CK:

Creatine kinase

CPT-1:

Carnitine palmitoyl transferase-1

CREB:

CAMP-response element-binding protein

DOMS:

Delayed onset muscle soreness

EIMD:

Exercise-induced muscle damage

E2:

17-β-Estradiol

EF:

Early follicular

ER:

Estrogen receptor

ERE:

Estrogen response elements

ERK:

Extracellular signal-related kinases

FABPc:

Fatty acid binding protein

FAS:

Fatty acid synthase

FATmax:

Exercise intensity at maximal fat oxidation

FATP:

Fatty acid transport protein

FOXO1:

Forkhead box protein O1

FSH:

Follicle-stimulating hormone

FSR:

Fractional protein synthetic rate

G6Pc:

Glucose-6-phosphotase

GLUT4:

Glucose transporter 4

GnRH:

Gonadotropin-releasing hormone

GPER:

G-protein estrogen receptor

β-HAD:

β-Hydroxyacyl-CoA dehydrogenase

IMTG:

Intramuscular triglyceride

IRS:

Insulin receptor substrate

LCFA:

Long chain fatty acid

LF:

Late follicular

LH:

Luteinizing hormone

LPL:

Lipoprotein lipase

MCAD:

Medium-chain fatty acyl-CoA dehydrogenase

MF:

Mid-follicular

ML:

Mid-luteal

mPR:

Membrane progestin receptors

mtGPAT:

Mitochondrial glycerol-3-phosphate acyl transferase

mtTFA:

Mitochondrial transcription factor A

Myo-D:

Myogenic differentiation factor D

NFκB:

Nuclear factor kappa-B

NRF-1:

Nuclear respiratory factor-1

OC:

Oral contraceptive

OVX:

Ovariectomized

p38MAPK:

P38 mitogen activated protein kinase

P4:

Progesterone

Pax7:

Paired box homeotic gene 7

PDK-1:

Phosphoinositide-dependent protein kinase-1

PDK-4:

Pyruvate dehydrogenase kinase 4

PEPCK:

Phosphoenolpyruvate-carboxykinase

PGRMC:

Progesterone G-protein receptor membrane complex

PI3K:

Phosphoinositide-3-kinase

PPAR:

Peroxisome proliferator-activated receptor

PR:

Progesterone receptor

PRE:

Progesterone response elements

Ra:

Rate of appearance

Rac1:

Ras-related C3 botulinum toxin substrate 1

Rd:

Rate of disappearance

RDI:

Recommended daily intake

Slc2a4:

Solute carrier family 2 member 4

SOD:

Superoxide dismutase

SP-1:

Specific protein 1

SREBP1c:

Sterol regulatory element-binding protein 1c

T3:

Triiodothyronine

T4:

Thyroxine

TBC1D:

TBC1Domain family member

TCA:

Tricarboxylic acid

TFPα:

Trifunctional protein alpha

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Authors and Affiliations

  1. School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

    Tanja Oosthuyse

  2. Division of Physiological Sciences, Department of Human Biology, University of Cape Town, Sports Science Institute of South Africa, Boundary Road, Newlands, Cape Town, 7700, South Africa

    Tanja Oosthuyse

  3. Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK

    Juliette A. Strauss

  4. Department of Exercise and Sport Science, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Anthony C. Hackney

Authors
  1. Tanja Oosthuyse
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  2. Juliette A. Strauss
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  3. Anthony C. Hackney
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Corresponding author

Correspondence to Tanja Oosthuyse.

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Author contribution

TO, JAS and ACH, conceived the review design; TO drafted the manuscript; TO, JAS and ACH edited, revised, and approved the final version of the manuscript.

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Preparation of this manuscript required no financial support.

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The authors have no conflict of interests, financial or otherwise to declare.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Communicated by Michael I Lindinger.

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Oosthuyse, T., Strauss, J.A. & Hackney, A.C. Understanding the female athlete: molecular mechanisms underpinning menstrual phase differences in exercise metabolism. Eur J Appl Physiol 123, 423–450 (2023). https://doi.org/10.1007/s00421-022-05090-3

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