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Examining the role of physical activity interventions in modulating androgens and cardiovascular health in postmenopausal females: A narrative review

Open AccessPublished:November 08, 2022DOI:https://doi.org/10.1016/j.cjco.2022.10.008

      Abstract

      Growing literature has examined the role of physical activity (PA) in modifying the effects of estrogen withdrawal on cardiovascular health in postmenopausal females, yet the impact of PA on androgens is less clear. Changes in androgen concentrations following regular PA may improve cardiovascular health. This narrative review summarized the literature assessing the impact of PA interventions on androgens in postmenopausal females. The association between changes in androgen concentrations and cardiovascular health following PA programs was also examined. Randomized controlled trials were included if they: (i) implemented a PA program of any type and duration in postmenopausal females; and (ii) measured changes in androgen concentrations. Following PA interventions, no changes in androstenedione, conflicting changes in dehydroepiandrosterone/ dehydroepiandrosterone-sulfate, and increases in sex hormone-binding globulin (SHBG) concentrations were found. Total testosterone decreased following aerobic PA but increased after resistance training. Most aerobic PA interventions led to reductions in free testosterone. A combination of caloric restriction and/or fat loss enhanced the influence of PA on most androgens. Evidence exploring the relationship between changes in androgens and cardiovascular health indicators was scarce and inconsistent. PA has shown promise in modifying the concentrations of some androgens (free and total testosterone, SHBG), and remains a well-known beneficial adjuvant option for postmenopausal females to manage their cardiovascular health. Fat loss influences the effect of PA on androgens, however, the synergistic role of PA and androgens on cardiovascular health merits further examination. Many research gaps in the relationship between PA, androgens and cardiovascular disease in postmenopausal females remain.

      Graphical abstract

      Key words

      INTRODUCTION

      Cardiovascular disease (CVD) is the leading cause of premature death in females over 50 years of age in developed countries.
      • Garcia M.
      • Mulvagh S.L.
      • Merz C.N.
      • Buring J.E.
      • Manson J.E.
      Cardiovascular disease in women: clinical perspectives.
      During their reproductive years, females have a lower risk of CVD than males, yet, following menopause this advantage disappears.

      Mulvagh SL, Mullen K-A, Nerenberg KA, et al. The Canadian women’s heart health alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women Chapter 4: Sex- and gender-unique disparities: CVD across the lifespan of a woman. CJC Open. 2022.

      Menopause is a female-specific risk factor for CVD, independent of natural aging.
      • Davis S.R.
      • Lambrinoudaki I.
      • Lumsden M.
      • et al.
      It occurs at a median age of 51 years,

      Mulvagh SL, Mullen K-A, Nerenberg KA, et al. The Canadian women’s heart health alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women Chapter 4: Sex- and gender-unique disparities: CVD across the lifespan of a woman. CJC Open. 2022.

      and is characterized by a change in hormonal milieu resulting in the cessation of ovarian estrogen production, while the ovaries continue to synthesize and secrete testosterone (an androgen).
      • El Khoudary S.R.
      • Aggarwal B.
      • Beckie T.M.
      • et al.
      Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association.
      In turn, the relative influence of androgens becomes more prominent after estrogen concentrations decrease post menopause.
      • Labrie F.
      Intracrinology and menopause: the science describing the cell-specific intracellular formation of estrogens and androgens from DHEA and their strictly local action and inactivation in peripheral tissues.
      Alterations in the concentrations of sex hormones following menopause impact cardiovascular health.
      • Davis S.R.
      • Lambrinoudaki I.
      • Lumsden M.
      • et al.
      ,
      • Vitale C.
      • Fini M.
      • Speziale G.
      • Chierchia S.
      Gender differences in the cardiovascular effects of sex hormones.
      Previous research on the relationship between menopause and increased CVD risk has primarily focused on decreased estrogen concentrations.

      Mulvagh SL, Mullen K-A, Nerenberg KA, et al. The Canadian women’s heart health alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women Chapter 4: Sex- and gender-unique disparities: CVD across the lifespan of a woman. CJC Open. 2022.

      These outcomes include evolution of a proatherogenic lipid profile and re-distribution of fat to visceral depositions,
      • Davis S.R.
      • Lambrinoudaki I.
      • Lumsden M.
      • et al.
      development of subclinical vascular disease,
      • El Khoudary S.R.
      • Aggarwal B.
      • Beckie T.M.
      • et al.
      Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association.
      ,
      • Montalcini T.
      • Gorgone G.
      • Gazzaruso C.
      • Sesti G.
      • Perticone F.
      • Pujia A.
      Endogenous testosterone and endothelial function in postmenopausal women.
      and increased blood pressure
      • Son M.K.
      • Lim N.-K.
      • Lim J.-Y.
      • et al.
      Difference in blood pressure between early and late menopausal transition was significant in healthy Korean women.
      (see Figure 1). However, the literature regarding the role of endogenous androgens on cardiovascular health in postmenopausal females is conflicting (see Androgens and cardiovascular health below). Many studies have attempted to characterize the relationship, but focused on sex-related differences in cardiovascular indicators
      • Vitale C.
      • Mendelsohn M.E.
      • Rosano G.M.C.
      Gender differences in the cardiovascular effect of sex hormones.
      or in females that have had androgenic therapy.
      • Spoletini I.
      • Vitale C.
      • Pelliccia F.
      • Fossati C.
      • Rosano G.M.
      Androgens and cardiovascular disease in postmenopausal women: a systematic review.
      While menopausal hormone therapy (MHT) has historically been considered cardioprotective, it is no longer recommended for primary and secondary prevention against CVD.
      • Abramson B.L.
      • Black D.R.
      • Christakis M.K.
      • Fortier M.
      • Wolfman W.
      Guideline No. 422e: Menopause and Cardiovascular Disease.
      Similarly, in 2019, a Global Consensus Position Statement endorsed by ten regulatory societies declared there was insufficient data to recommend testosterone therapy for CVD prevention or treatment in postmenopausal females.
      • Davis S.R.
      • Baber R.
      • Panay N.
      • et al.
      Global consensus position statement on the use of testosterone therapy for women.
      In fact, they recommended against the use of oral testosterone therapy as it has been associated with decreased high-density lipoprotein and increased low-density lipoprotein.
      • Davis S.R.
      • Baber R.
      • Panay N.
      • et al.
      Global consensus position statement on the use of testosterone therapy for women.
      There are substantial gaps in female-specific CVD research, as most CVD-related clinical trials were comprised of more than 85% males and ∼66% of all CVD research has focused on males.

      Foundation HaS. Ms. Understood: Heart and Stroke 2018 Heart Report: Heart and Stroke Foundation; 2018:20.

      These assumptions and gaps in key clinical knowledge warrant a narrative investigation of the influence of androgens on CVD in postmenopausal females.
      Figure thumbnail gr1
      Figure 1Rationale for the need to assess the impact of physical activity interventions on androgen concentrations and cardiovascular health in postmenopausal females. CV, cardiovascular; CVD, cardiovascular disease; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone-sulfate; PA, physical activity; PMF, postmenopausal females.
      Physical activity (PA) is a safe, cost-effective strategy that has been shown to improve modifiable CVD risk factors associated with aging and postmenopausal status.
      • Garcia M.
      • Mulvagh S.L.
      • Merz C.N.
      • Buring J.E.
      • Manson J.E.
      Cardiovascular disease in women: clinical perspectives.
      ,
      • Mendoza N.
      • De Teresa C.
      • Cano A.
      • et al.
      Benefits of physical exercise in postmenopausal women.
      For example, moderate-intensity aerobic PA has been shown to reduce cortisol to dehydroepiandrosterone (DHEA) ratios, fasting glucose, inflammation, and blood pressure.
      • Bucciarelli V.
      • Bianco F.
      • Mucedola F.
      • et al.
      Effect of adherence to physical exercise on cardiometabolic profile in postmenopausal women.
      Increasing minutes of aerobic PA has been associated with decreased adiposity in postmenopausal females.
      • Gonzalo-Encabo P.
      • McNeil J.
      • Pérez-López A.
      • Valadés D.
      • Courneya K.S.
      • Friedenreich C.M.
      Dose-response effects of aerobic exercise on adiposity markers in postmenopausal women: pooled analyses from two randomized controlled trials.
      The increase in cardiorespiratory fitness (CRF) following regular PA also lowers the risk of CVD
      • Haddock B.L.
      • Hopp H.P.
      • Mason J.J.
      • Blix G.
      • Blair S.N.
      Cardiorespiratory fitness and cardiovascular disease risk factors in postmenopausal women.
      and attenuates the arterial stiffness that accompanies aging.
      • Mendoza N.
      • De Teresa C.
      • Cano A.
      • et al.
      Benefits of physical exercise in postmenopausal women.
      For an in-depth review of the negative effects of menopause on CVD risk factors and the positive impact of PA on CVD in postmenopausal females, the reader is referred to El Khoudary et al
      • El Khoudary S.R.
      • Aggarwal B.
      • Beckie T.M.
      • et al.
      Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association.
      and Mendoza et al,
      • Mendoza N.
      • De Teresa C.
      • Cano A.
      • et al.
      Benefits of physical exercise in postmenopausal women.
      respectively.
      Given the remarkable health benefits of PA, the World Health Organization and Canadian Society for Exercise Physiology recommend adults (18-64 years) and older adults (64+ years) accumulate at least 150 to 300 minutes of moderate-intensity PA or 75 to 150 minutes of vigorous-intensity PA per week, and muscle-strengthening activities on two or more days a week.
      • Bull F.C.
      • Al-Ansari S.S.
      • Biddle S.
      • et al.
      World Health Organization 2020 guidelines on physical activity and sedentary behaviour.
      ,

      Physiology CSfE. 24-hour movement guideline for adults (18-64 years and 65+ years)2021.

      However, females are often less physically active than males.

      Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary health statistics for U.S. adults: National Health Interview Survey, 2010. Vital Health Stat 10. 2012:1-207.

      Only 16.6% of females at least 40 years of age in Canada meet the PA recommendations measured with accelerometers.21In a national cohort of previously inactive American adults over 60 years old, those who increased their PA frequency to 3 to 4 times per week significantly lowered their risk of CVD events when compared to those who remained inactive.
      • Kim K.
      • Choi S.
      • Hwang S.E.
      • et al.
      Changes in exercise frequency and cardiovascular outcomes in older adults.
      Menopause may, thus, be a key period to encourage females to become physically active. If PA is an effective preventative therapy to reverse the negative cardiovascular consequences that follow altered hormone concentrations in postmenopausal females,
      • Bucciarelli V.
      • Bianco F.
      • Mucedola F.
      • et al.
      Effect of adherence to physical exercise on cardiometabolic profile in postmenopausal women.
      the role of PA in modulating the specific effects of androgens on cardiovascular health must be considered.
      Recent evidence suggests an interplay between fat loss, androgens, and PA in subpopulations of females, including those at increased risk of breast cancer and with polycystic ovary syndrome (PCOS). Gonzalo-Encabo et al. investigated the role of PA on sex hormones and breast cancer risk in obese and overweight postmenopausal females and found that aerobic training, when compared to aerobic combined with resistance training, had a stronger impact on restoring sex hormone homeostasis (i.e. decreasing estrogens and androgens [decreased DHEA, testosterone, androstenedione] and increasing SHBG]).
      • Gonzalo-Encabo P.
      • Valadés D.
      • De Cos A.I.
      • García-Honduvilla N.
      • Pérez-López A.
      Effects of exercise on circulating levels of sex hormones in overweight and obese postmenopausal women: a systematic review.
      This effect was more pronounced when combined with exercise-induced weight loss.
      • Gonzalo-Encabo P.
      • Valadés D.
      • De Cos A.I.
      • García-Honduvilla N.
      • Pérez-López A.
      Effects of exercise on circulating levels of sex hormones in overweight and obese postmenopausal women: a systematic review.
      Similarly, a systematic review including females of all ages with PCOS revealed that vigorous-intensity aerobic PA was associated with the largest improvements in insulin sensitivity, and resistance training lowered androgen concentrations more than aerobic, aquatic high-intensity interval training, or yoga PA modalities.
      • Shele G.
      • Genkil J.
      • Speelman D.
      A systematic review of the effects of exercise on hormones in women with polycystic ovary syndrome.
      However, a consensus on the influence of PA in altering androgen concentrations in a larger inclusive population of postmenopausal females has not been reached.
      • Enea C.
      • Boisseau N.
      • Fargeas-Gluck M.A.
      • Diaz V.
      • Dugué B.
      Circulating androgens in women.
      Given the altered sex hormone profile that follows menopause and its subsequent influence on CVD risk, alternative preventative strategies that positively impact sex hormones and cardiovascular health are crucial. Changes in androgen concentrations following regular PA may improve cardiovascular health (see Figure 1). To address the limited literature surrounding androgens and CVD in postmenopausal females, there have been calls for action by experts in the field to investigate the sex-specific effects of androgens on CVD risk
      • Davis S.R.
      • Wahlin-Jacobsen S.
      Testosterone in women—the clinical significance.
      • Squiers G.T.
      • McLellan M.A.
      • Ilinykh A.
      • Branca J.
      • Rosenthal N.A.
      • Pinto A.R.
      Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones.
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      and whether regular PA can modulate circulating androgen concentrations
      • Enea C.
      • Boisseau N.
      • Fargeas-Gluck M.A.
      • Diaz V.
      • Dugué B.
      Circulating androgens in women.
      in postmenopausal females. The aims of this narrative review were to: (1) provide the reader with a background in the production and function of androgens, alterations of androgens following menopause, and their potential impact on cardiovascular health; and, (2) summarize the existing literature assessing the impact of PA interventions on androgen concentrations in postmenopausal females. As a secondary aim, we examined the association between changes in androgen concentrations and cardiovascular health indicators (e.g. body mass and composition, blood pressure, CRF, blood biomarkers) following a PA program.

      ANDROGENS AND MENOPAUSE

      Androgens are essential steroid hormones with important roles in sexual function.
      • Davis S.R.
      • Wahlin-Jacobsen S.
      Testosterone in women—the clinical significance.
      ,
      • Brzozowska M.
      • Lewiński A.
      Changes of androgens levels in menopausal women.
      They are one of four steroid hormone groups (including progesterone, estrogens, and corticoids) which originate from a common cholesterol precursor (See Figure 2). Sources of androgens are either by direct secretion from endocrine glands (i.e. ovaries and adrenals) or indirect bioconversion of circulating androgenic prohormones into active hormones by enzymatic activity in peripheral tissues (see Figure 3). With the loss of ovarian follicular activity at menopause, the adrenal gland acts as the primary source of androgens: DHEA, dehydroepiandrosterone-sulfate (DHEA-S), and androstenedione become major precursors for the extragonadal production of androgens in postmenopausal females.

      Tulandi T, Gelfand M. Androgens and reproductive aging: CRC Press; 2005.

      Figure thumbnail gr2
      Figure 2Pathway of major ovarian and adrenal sex steroid synthesis. The synthesis of adrenal steroids aldosterone and cortisol have been omitted for the purposes of this review.
      Figure thumbnail gr3
      Figure 3A schematic representation of sources of androgen in postmenopausal females. 1) ovary, 2) adrenal gland, and 3) peripheral tissues. DHEA is a major source of androgens in postmenopausal females and is converted into testosterone and dihydrotestosterone for action in target peripheral tissues. All androgens must be bound to sex hormone binding globulin to enter the blood stream.
      DHEA and androstenedione have little androgenic activity and are quickly converted into testosterone in peripheral tissues.

      Gupta MK, Chia S-Y. Ovarian Hormones: Structure, Biosynthesis, Function, Mechanism of Action, and Laboratory Diagnosis. In: Falcone T, Hurd WW, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. New York, NY: Springer New York; 2013:1-30.

      Testosterone can then act directly on androgen receptors, be reduced to dihydrotestosterone by enzymatic action at target tissues (i.e. ovaries, skin, and liver), or be aromatized to estradiol.
      • Davis S.R.
      • Baber R.
      • Panay N.
      • et al.
      Global consensus position statement on the use of testosterone therapy for women.
      ,
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      Testosterone and dihydrotestosterone are considered the most potent source of androgens in terms of affinity for androgen receptors.
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      Androgen physiology is highly dependent upon the binding of sex steroids to SHBG in circulating blood.
      • Hammond G.L.
      Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.
      Only unbound androgens bind to steroid receptors in peripheral tissues.
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      SHBG has a high affinity for testosterone and dihydrotestosterone, but low affinity for DHEA. SHBG does not bind to DHEA-S.
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      A small proportion (2%) of testosterone remains unbound and biologically active, measured as ‘free’ testosterone.
      • Hammond G.L.
      Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.
      ‘Total’ testosterone refers to the bound form of testosterone to SHBG plus the amount of unbound, free testosterone. A surrogate measure of free testosterone is the free androgen index (FAI), which is a ratio of total testosterone to SHBG and a validated marker of androgenicity in postmenopausal females.
      • Georgiopoulos G.
      • Kontogiannis C.
      • Lambrinoudaki I.
      • Rizos D.
      • Stamatelopoulos K.
      Free androgen index as a biomarker of increased cardiovascular risk in postmenopausal women.
      Therefore, androgen activity is dependent upon endocrine secretion, peripheral bioconversion, and SHBG concentrations.

      Alterations in androgen concentrations after menopause

      In postmenopausal females, circulating estrogen concentrations are lower when compared to premenopausal levels, contributing to an relative increase in androgenic concentrations.
      • Labrie F.
      • Luu-The V.
      • Labrie C.
      • et al.
      Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone.
      More specifically, androgen production decreases over the life span, including after menopause.
      • Labrie F.
      • Luu-The V.
      • Labrie C.
      • et al.
      Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone.
      • Davison S.L.
      • Bell R.
      • Donath S.
      • Montalto J.G.
      • Davis S.R.
      Androgen levels in adult females: changes with age, menopause, and oophorectomy.
      • Wierman M.E.
      • Arlt W.
      • Basson R.
      • et al.
      Androgen therapy in women: A reappraisal: An Endocrine Society Clinical Practice Guideline.
      • Zumoff B.
      • Strain G.W.
      • Miller L.K.
      • Rosner W.
      Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women.
      Estrogen production also decreases after menopause,
      • Davis S.R.
      • Lambrinoudaki I.
      • Lumsden M.
      • et al.
      but to a greater extent allowing the relative influence of androgens to become more pronounced. DHEA concentrations decline up to 60% prior to menopause and continue decreasing throughout the lifespan.
      • Labrie F.
      • Bélanger A.
      • Cusan L.
      • Gomez J.L.
      • Candas B.
      Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging.
      Similarly, testosterone decreases with reproductive aging,
      • Wierman M.E.
      • Arlt W.
      • Basson R.
      • et al.
      Androgen therapy in women: A reappraisal: An Endocrine Society Clinical Practice Guideline.
      up to 50% in females in their 40s when compared to 30s,
      • Zumoff B.
      • Strain G.W.
      • Miller L.K.
      • Rosner W.
      Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women.
      and plateaus after the age of 65.
      • Davis S.R.
      • Baber R.
      • Panay N.
      • et al.
      Global consensus position statement on the use of testosterone therapy for women.
      This may reflect an age-related reduction rather than the influence of menopause. Minimal decreases in androstenedione have been observed after menopause.
      • Davison S.L.
      • Bell R.
      • Donath S.
      • Montalto J.G.
      • Davis S.R.
      Androgen levels in adult females: changes with age, menopause, and oophorectomy.
      Finally, SHBG concentrations decline steadily throughout the menopausal transition, increasing the FAI.
      • Hammond G.L.
      Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.
      ,
      • Sowers M.F.R.
      • Zheng H.
      • McConnell D.
      • Nan B.
      • Karvonen-Gutierrez C.A.
      • Randolph Jr., J.F.
      Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging.
      The cardiovascular changes that accompany the increased androgen concentrations following menopause are poorly understood.

      Androgens and cardiovascular health

      Testosterone and the risk of cardiovascular disease

      Conflicting results have been reported from longitudinal cohort studies such that both high (i.e. in n=4,600 pre and postmenopausal
      • Benn M.
      • Voss Sidsel S.
      • Holmegard Haya N.
      • Jensen Gorm B.
      • Tybjærg-Hansen A.
      • Nordestgaard Børge G.
      Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women.
      ; n=2,634 postmenopausal
      • Zhao D.
      • Guallar E.
      • Ouyang P.
      • et al.
      Endogenous sex hormones and incident cardiovascular disease in post-menopausal women.
      females) and low total testosterone (in n=2,914 pre and postmenopausal females
      • Sievers C.
      • Klotsche J.
      • Pieper L.
      • et al.
      Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients.
      ) concentrations have been associated with increased CVD risk. For instance, females with high (95th percentile) testosterone concentrations showed a 68% greater risk of ischemic heart disease when compared to those with lower (10th to 89th percentile) concentrations.
      • Benn M.
      • Voss Sidsel S.
      • Holmegard Haya N.
      • Jensen Gorm B.
      • Tybjærg-Hansen A.
      • Nordestgaard Børge G.
      Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women.
      A systematic review (n=23 RCTs studying exogenous androgen administration) concluded that chronic states of hyperandrogenism (i.e. high testosterone and low SHBG) contribute to increased CVD risk.
      • Spoletini I.
      • Vitale C.
      • Pelliccia F.
      • Fossati C.
      • Rosano G.M.C.
      Androgens and cardiovascular disease in postmenopausal women: a systematic review.
      Yet, low total testosterone has been associated with an increased risk of cardiovascular events (i.e. angina pectoris, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass surgery, stroke, transient ischemic attack) (hazard ratio 0.68 [95% CI 0.48-0.97]) after adjustment for BMI >25 kg/m2, age, and smoking in postmenopausal females.
      • Sievers C.
      • Klotsche J.
      • Pieper L.
      • et al.
      Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients.
      Moreover, in a prospective population-based trial, postmenopausal females (n=639) with the highest free testosterone (≥63 pg/mL) and lowest total testosterone (≤80 pg/mL) concentrations had the highest incidence of cardiovascular events, even after adjustment for PA levels, BMI, and other CVD risk factors.
      • Laughlin G.A.
      • Goodell V.
      • Barrett-Connor E.
      Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women.
      In summary, both high and low levels of total testosterone may have negative health consequences, and it remains unclear in the literature which association may be worse. This suggests there may be an intermediate physiological range that may benefit cardiovascular health, however inconsistent findings limit our current understanding of these pathophysiologic mechanisms.
      • Wierman M.E.
      • Arlt W.
      • Basson R.
      • et al.
      Androgen therapy in women: A reappraisal: An Endocrine Society Clinical Practice Guideline.
      ,
      • Laughlin G.A.
      • Goodell V.
      • Barrett-Connor E.
      Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women.
      ,
      • Manolakou P.
      • Angelopoulou R.
      • Bakoyiannis C.
      • Bastounis E.
      The effects of endogenous and exogenous androgens on cardiovascular disease risk factors and progression.
      Finally, low SHBG has been positively associated with an increased CVD risk in narrative
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      ,
      • Wierman M.E.
      • Arlt W.
      • Basson R.
      • et al.
      Androgen therapy in women: A reappraisal: An Endocrine Society Clinical Practice Guideline.
      and systematic reviews.
      • Spoletini I.
      • Vitale C.
      • Pelliccia F.
      • Fossati C.
      • Rosano G.M.C.
      Androgens and cardiovascular disease in postmenopausal women: a systematic review.
      Recent expert reviews have postulated that the development of CVD may be more influenced by low SHBG than testosterone concentrations,
      • Shifren J.L.
      • Davis S.R.
      Androgens in postmenopausal women: a review.
      ,
      • Wierman M.E.
      • Arlt W.
      • Basson R.
      • et al.
      Androgen therapy in women: A reappraisal: An Endocrine Society Clinical Practice Guideline.
      which may be particularly relevant in postmenopausal females who have low serum SHBG.
      • Hammond G.L.
      Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.
      ,
      • Sowers M.F.R.
      • Zheng H.
      • McConnell D.
      • Nan B.
      • Karvonen-Gutierrez C.A.
      • Randolph Jr., J.F.
      Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging.

      Androgens and vascular disease progression

      In postmenopausal females, higher androstenedione and free testosterone concentrations have been significantly associated with reduced carotid artery intima-media thickness, a marker of atherosclerosis.
      • Manolakou P.
      • Angelopoulou R.
      • Bakoyiannis C.
      • Bastounis E.
      The effects of endogenous and exogenous androgens on cardiovascular disease risk factors and progression.
      Independent of CVD risk factors (i.e. BMI, insulin resistance, systolic blood pressure, and lipids), higher serum total testosterone and FAI corresponded to increased carotid artery intima-media thickness, and lower DHEA-S was associated with arterial stiffness.
      • Creatsa M.
      • Armeni E.
      • Stamatelopoulos K.
      • et al.
      Circulating androgen levels are associated with subclinical atherosclerosis and arterial stiffness in healthy recently menopausal women.
      Indeed, an increased incidence of atherosclerosis has been observed in females with PCOS who may have marked hyperandrogenism, even after adjusting for BMI.
      • Talbott E.O.
      • Zborowski J.
      • Rager J.
      • Stragand J.R.
      Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women?.
      Therefore, while increased androgens appear to influence the development of atherosclerosis, the relative influence of each steroid independently has not been established.

      Androgens and insulin resistance

      Type 2 diabetes has been shown to increase the risk of coronary artery disease mortality more strongly in females when compared to males (i.e. 3.5- vs. 2-fold increase, respectively).
      • Huxley R.
      • Barzi F.
      • Woodward M.
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      A systematic review of prospective and cross-sectional studies by Ding et al. determined that, when compared to controls, total testosterone (range: 449.6 to 605.2 ng/dL) was significantly higher in females with type 2 diabetes (mean difference, 6.1 ng/dL; 95% CI, 2.3 to 10.1; p<0.001 for sex difference).
      • Ding E.L.
      • Song Y.
      • Malik V.S.
      • Liu S.
      Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.
      Moreover, females with higher SHBG concentrations (>60 nmol/L) had an 80% lower risk of type 2 diabetes (RR, 0.20; 95% CI, 0.12 to 0.30), whilst males had a 52% lower risk.
      • Ding E.L.
      • Song Y.
      • Malik V.S.
      • Liu S.
      Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.
      This review conversely found that high SHBG concentrations led to low free testosterone, suggesting high SHBG may protect against the adverse effects of free testosterone.
      • Ding E.L.
      • Song Y.
      • Malik V.S.
      • Liu S.
      Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.
      SHBG has been established as an independent marker for insulin resistance, and low SHBG has been associated with the development of obesity, independent of estrogen and androgen concentrations. Insulin resistance can stimulate the ovarian production of androgens while also inhibiting SHBG, via increasing insulin-like growth factor (IGF-1).
      • Davis S.R.
      • Robinson P.J.
      • Moufarege A.
      • Bell R.J.
      The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women.
      ,
      • Bianchi V.E.
      • Bresciani E.
      • Meanti R.
      • Rizzi L.
      • Omeljaniuk R.J.
      • Torsello A.
      The role of androgens in women's health and wellbeing.
      Finally, recent evidence has shown a positive correlation between left ventricular hypertrophy, increased FAI, and decreased SHBG in postmenopausal hypertensive females, directly linking CVD with androgen concentrations outside of expected physiologic ranges.
      • Jianshu C.
      • Qiongying W.
      • Ying P.
      • Ningyin L.
      • junchen H.
      • Jing Y.
      Association of free androgen index and sex hormone–binding globulin and left ventricular hypertrophy in postmenopausal hypertensive women.
      Endogenous androgens may have sex-specific modulation of glycemic control and onset of type 2 diabetes, influencing cardiovascular health largely through the effects of SHBG.

      Androgens and body composition

      Adipose tissue is a potent source of androgen metabolism through peripheral tissue bioconversion, and increased adiposity may heighten androgen concentrations in postmenopausal females with higher BMI.
      • Enea C.
      • Boisseau N.
      • Fargeas-Gluck M.A.
      • Diaz V.
      • Dugué B.
      Circulating androgens in women.
      Changes accompanying menopause include a redistribution of fat to the abdominal area.
      • Kostakis E.K.
      • Gkioni L.N.
      • Macut D.
      • Mastorakos G.
      Androgens in menopausal women: not only polycystic ovary syndrome.
      Increased abdominal circumference has also been independently associated with insulin resistance, increased LDL, serum triglycerides, and blood pressure.
      • Vitale C.
      • Fini M.
      • Speziale G.
      • Chierchia S.
      Gender differences in the cardiovascular effects of sex hormones.
      Finding strategies to reduce adipose tissue, increase SHBG, and improve insulin resistance may, therefore, alter androgen concentrations in postmenopausal females.

      METHODS

      To summarize the existing literature a search was created by a medical research librarian (SV) in collaboration with the project leads (CE, JR). The search was created in MEDLINE using a combination of key terms and index headings related to postmenopausal females, androgens, and PA and then translated to the Cochrane Central Register of Controlled Trials, Embase, and CINAHL (see Supplemental Table S1-4). The searches were conducted on August 10, 2020 and updated on December 17, 2021. Where possible, French and English limits were applied. Randomized controlled trials (RCTs) were included if they implemented a PA program of any type and duration in postmenopausal females and measured changes in androgen (i.e., androstenedione, DHEA, DHEA-S, total/free testosterone, and/or SHBG) concentrations. Females of any health status were included if they: (i) were >40 years of age (as menopause before this time is considered premature ovarian insufficiency
      • Davis S.R.
      • Lambrinoudaki I.
      • Lumsden M.
      • et al.
      ), and >12 months had passed since their last known period (ii) had no prior history of oophorectomy, and (iii) did not take MHT. In studies with mixed populations (e.g., both sexes, females on MHT, only data from postmenopausal females not taking MHT were extracted and included. Traditional cardiovascular health indicators (e.g., BMI, body composition, CRF, blood pressure, blood biomarkers) reported at baseline and follow up in at least 3 studies were extracted by the authors.

      RESULTS

      Study characteristics

      A total of 3,253 articles were identified for this review; following the removal of duplicates (n=1245), 2,008 articles were screened by title and abstract. Full-text screening was conducted in 138 articles and 15 RCTs were deemed eligible for inclusion (see Supplemental Figure S1). In two studies that included ineligible populations (i.e. females on MHT) [n=3954 n=1655]) only data from postmenopausal females not taking HRT in the PA group were extracted. Characteristics of the included RCTs implementing a PA program and measuring androgen concentrations in postmenopausal females are presented in Table 1. Most females were sedentary
      • Figueroa A.
      • Going S.
      • Milliken L.
      • et al.
      Effects of Exercise Training and Hormone Replacement Therapy on Lean and Fat Mass in Postmenopausal Women.
      ,
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      • Ward L.J.
      • Nilsson S.
      • Hammar M.
      • et al.
      Resistance training decreases plasma levels of adipokines in postmenopausal women.
      and overweight or obese,
      • Figueroa A.
      • Going S.
      • Milliken L.
      • et al.
      Effects of Exercise Training and Hormone Replacement Therapy on Lean and Fat Mass in Postmenopausal Women.
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      ,
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      with a mean age between 53 and 70 years. There was high heterogeneity in the frequency (2-5 days/week), intensity (light, moderate, and vigorous), duration (30-75 minutes/session), and total length (12 weeks - 12 months) of the PA interventions. These interventions were categorized as aerobic PA,
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      resistance training,
      • Figueroa A.
      • Going S.
      • Milliken L.
      • et al.
      Effects of Exercise Training and Hormone Replacement Therapy on Lean and Fat Mass in Postmenopausal Women.
      ,
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      ,
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      ,
      • Ward L.J.
      • Nilsson S.
      • Hammar M.
      • et al.
      Resistance training decreases plasma levels of adipokines in postmenopausal women.
      or combined aerobic and resistance training (see Table 1).
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      See Figure 4 for a visual representation of the changes in androgen concentrations following aerobic and/or resistance training.
      Table 1Characteristics of RCTs implementing a physical activity program in postmenopausal females.
      Participant CharacteristicsIntervention Characteristics
      NAge mean (SD) or range of groupsInclusion criteriaActivityFrequencyIntensityDurationLengthCo-intervention/ control groupHormone(s) studied
      Aerobic Exercise
      Campbell et al. 2012

      USA
      439 from the ‘New’ RCTPA: 58 (5)

      Diet + PA: 58 (5)

      Diet: 58 (6)

      C: 57 (4)
      Healthy, BMI >25, < 100 min/wk PA PMF 50-75yoSupervised + at-home aerobic exercise (n=117)5 d/wk (3 onsite, 2 at home)Moderate- to-vigorous: 70-85% HRMax or 4+ METS≥45 min12 moDiet + PA (n=117)

      Diet: caloric restriction (n=118)

      C: maintain usual activities (n=87)
      Androstenedione

      SHBG

      Testosterone (free, total)
      Friedenreich et al.

      2010

      Canada
      320PA: 61 (5)

      C: 60 (5)
      Healthy, BMI 22-40

      <120 min/wk PA, PMF 50-74yo
      Supervised + at-home aerobic exercise (n=160)5 d/wk (3 onsite, 2 at home)70-80 % HRR≥45 min12 moC: maintain usual activities (n=160)Androstenedione

      SHBG

      Testosterone (free, total)
      Friedenreich et al.

      2015

      Canada
      400 from the BETA trialModerate: 60 (5)

      High: 59 (5)
      Healthy, BMI 22-40, <120 min/wk PA, PMF 50-74yoSupervised + at-home aerobic exercise5 d/wk (3 onsite, 2 at home)60-80% HRRModerate group: 30 min (n=200)

      High group: 60 min (n=200)
      12 moNo controlSHBG
      Kim & Kim, 2012

      South Korea
      30Total: 55 (3)Healthy, BF >32%, <40 min/wk PA, PMFSupervised aerobic dance (n=15)3 d/wk55-80 % HR max60 min16 wkC: maintain usual activities (n =15)SHBG
      McTiernan et al.

      2004

      USA

      173PA: 61 (7)

      C: 61 (7)
      Healthy, BMI ≥24, <60min/wk PA, PMF 50-79yoSupervised + at-home aerobic exercise (n=87)5 d/wk60-75 % HR max45 min12 moC: stretching exercises (1x/wk for 45 min)

      (n=86)
      Androstenedione

      DHEA

      DHEA-S

      Testosterone (free, total)
      Yoo et al.

      2010

      South Korea
      21PA: 70 (2)

      C: 71 (2)
      Healthy PMF >65 yoSupervised walking with ankle weights (1kg) (n=11)3 d/wk60% HRR60 min12 wkC: maintain usual activities (n=10)Testosterone (total)
      Resistance Training
      Copeland et al.

      2004

      Canada
      16PA: 53 (5)

      C: 54 (6)
      Healthy, sedentary PMF >50yoSupervised resistance training (n=8)3 d/wk10 RMNR12 wkC: unsupervised flexibility exercises 3 d/wk (n=8)DHEA

      Testosterone (total)
      Figueroa et al. 2003

      USA
      74PA: 57 (1)

      C: 57 (1)
      Healthy, sedentary PMF 40-65yoSupervised resistance training (n=24)3 d/wk70-80 % 1RM60-75 min12 moC: maintain usual activities (n=28)Androstenedione
      Nunes et al. 2019

      Brazil
      34Low: 64 (NR)

      High: 60 (NR)

      C: 59 (NR)
      Healthy, sedentary PMF 49-79yoResistance training:

      Low volume (3 sets) (n=10)

      High volume (6 sets) n=12)
      3 d/wk70% 1RMLow volume: ∼45 min

      High volume: ∼90 min
      16 wkC: stretching exercises 2x/wk (n=12)DHEA-S

      Testosterone (total)
      Orsatti et al. 2008

      Brazil
      43PA: 58 (8)

      C: 59 (6)
      Healthy, sedentary PMF 45-70yoSupervised resistance training (n=22)3 d/wk60-80% 1RM50-60 min16 wkC: maintain usual activities (n=21)Total testosterone
      Son et al. 2020

      South Korea
      20PA: 68 (1)

      C: 67 (1)
      Healthy, sedentary, Stage 1 HTN PMFSupervised resistance band training (n=10)3 d/wkIncreased progressively: 40-50% to 60-80% 1RM60 min12 wkC: supervised sedentary activities (n=10)DHEA-S
      Ward et al. 2020

      Sweden
      55PA: 58 (5)

      C: 55 (5)
      Healthy, sedentary (<75min/wk MVPA) PMF with vasomotor symptomsSupervised and at-home resistance training (n=26)3 d/wk8RMNR15wkC: remain sedentary (n=29)Testosterone

      SHBG
      Combined Aerobic and Resistance Training
      Gonzalo‐Encabo et al. 2020

      Spain
      35Median

      Endurance: 56

      Concurrent:58

      C: 57
      Healthy, BMI >25, <150 min/wk PA PMF 50-65yoSupervised endurance (n=10) or endurance + resistance (n=13) training3 d/wkEndurance: 55-75% HRR

      Resistance: 65% 1RM
      Endurance: 60 min of aerobic

      Concurrent: 20 min aerobic + resistance exercises
      12 wkC: maintain usual activities (n=12)DHEA-S

      Testosterone (free, total)

      SHBG
      Monninkhof et al.

      2009

      Netherlands
      189 from the SHAPE studyPA: 59 (5)

      C: 58 (4)
      Healthy, BMI >22, <120 min/wk PA PMF 50-69yoSupervised + at-home aerobic + resistance training (n=96)Supervised: 2 d/wk

      At home: 1 d/wk
      MVPASupervised: 60 min

      At home: 30 min
      12 moC: maintain usual activities (n=93)Androstenedione

      SHBG

      Testosterone (free, total)
      van Gemert et al.

      2015

      Netherlands
      243 from the SHAPE-2 trialPA: 59 (4)

      Diet: 60 (5)

      C: 60 (5)
      Healthy, <120 min/wk PA, BMI 25-35, PMF 50-69yoSupervised resistance + endurance training sessions, Nordic walking (n=98)2d/wk combined resistance + endurance training

      2d/wk Nordic walking
      Target HRR increased progressively. Resistance:

      1RM

      Endurance: 60-90% HRR

      Nordic: 60-65% HRR
      60 mins16 wkDiet only: restriction to 3500 kcal/wk & nutrition education group sessions (5x total, 1hr) (n=97)

      C: complete food diaries and usual activities (n=48)
      Androstenedione

      SHBG

      Testosterone (free, total)
      BF, body fat; BMI, body mass index; C, control; d, day; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulphate; HTN, hypertension; HRmax, heart rate maximum; HRR, heart rate reserve; METS, metabolic equivalent of task; min, minutes; mo, months; NR, not reported; N, number; PA, physical activity; PMF, postmenopausal females; RCT, randomized control trial; RM, repetition maximum; RPE, ratings of perceived exertion; SD, standard deviation; SHBG, sex hormone binding globulin; USA, United States of America; wk, week.; yo, years old
      Figure thumbnail gr4
      Figure 4A visual representation of changes in androgen concentrations following aerobic and/or resistance training. M, moderate; PA, physical activity; V, vigorous.

      Physical activity and androgen concentrations

      Physical activity and androstenedione

      Our findings demonstrate that studies implementing PA programs (n=554, 56, 58, 61, 66) did not elicit significant changes in androstenedione concentrations in postmenopausal females (see Table 2). Studies comparing PA of any intensity to control conditions (i.e. maintain usual activities, diet, or stretching exercises) over 12 months showed no changes in androstenedione in postmenopausal females in response to different PA modalities (i.e. aerobic exercise,
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      resistance training,
      • Figueroa A.
      • Going S.
      • Milliken L.
      • et al.
      Effects of Exercise Training and Hormone Replacement Therapy on Lean and Fat Mass in Postmenopausal Women.
      or combined aerobic and resistance training
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      ). This suggests androstenedione concentrations are not influenced by PA interventions regardless of the type, duration, or intensity in postmenopausal females.
      Table 2Changes in androgen hormone concentrations from baseline to follow up after a physical activity intervention.
      AuthorsUnits

      Groups
      AndrostenedioneDHEA or DHEA-STestosterone (free)Testosterone (total)SHBG
      Aerobic Activity
      Campbell et al.

      2012

      USA
      Mean (95% CI); Δ%pg/mL†-pg/mLpg/mL†nmol/L
      PA502 (466-541) to 496 (456-540); -1.2%-5.1 (4.7-5.5) to 4.9 (4.5-5.3); -4.5%

      ***vs. diet and PA

      *vs. diet
      248 (230-267) to 236 (216 to 257); -4.9%39.1 (35.9-42.6) to 38.8 (35.6-42.4); -0.7%

      ***vs. diet

      ***vs. diet and PA
      Diet511 (471-553) to 518 (477-562); +1.4%5.1 (4.7-5.6) to 4.6 (4.2-5.1); -10%

      ***vs. control

      *vs. diet and PA
      239 (219-260) to 236 (216 to 258); -0.9%35.8 (33-38.8) to 43.8 (40.4-47.5); +22.4%

      ***vs. control
      Diet + PA526 (491-564) to 508 (471-547); -3.5%-5.3 (4.9-5.7) to 4.5 (4.1-4.8); -15.6%

      ***vs. control
      239 (221-258) to 225 (208 to 243); -5.9%

      *vs. control
      34.1 (31.9-36.4) to 42.9 (40.2-45.6); +25.8%

      *** vs. control
      Control487 (439-540) to 494 (454-537); +1.5%-4.9 (4.4-5.6) to 5.1 (4.6-5.7); +2.6%228 (202-257) to 232 (209-257); +1.8%34.7 (31.5 - 38.2) to 33.7 (30.3-37.5); -2.7%
      Friedenreich et al.

      2010

      Canada
      Mean (95%CI)pg/mL-pg/mL†pg/mL†nmol/L
      PA578 (539-621) to 572 (537-610)-3.5 (3.2-3.8) to 3.3 (3.1-3.6)239 (223-258) to 234 (217-253)40.3 (37.5 to 43.4) to 41.9 38.9 to 45.1 ***vs. control
      Control553 (514-595) to 577 (534-624)-3.5 (3.2-3.8) to 3.5 (3.3-3.9)231 (213-251) to 237 (218-257)38.1 (35.7-40.8) to 38.4 (35.9-41.1)
      Friedenreich et al.

      2015

      Canada
      Geometric Mean (95%CI); Δ%----nmol/L
      Moderate (150min/wk PA)----43.2 (40.6, 46.0) to 47.4 (44.6, 50.4); +9.6%
      High (300min/wk PA)----47.6 (44.7, 50.8) to 50.7 (47.7, 53.9); +6.4%
      Kim & Kim,

      2012

      South Korea
      Mean (SD)----nmol/L
      PA----43.3 (9.2) to 46.0 (10.0)

      ***vs. control

      **within group
      Control----44.2 (8.1) to 42.2 (8.8)

      *within group
      McTiernan et al. 2004

      USA
      Geometric Mean (95%Cl)pg/mLDHEA (ng/mL);

      DHEA-S (ug/dL)
      pg/mLpg/mL-
      PA533 (494-575) to 480 (447-516)2.19 (1.93-2.49) to 1.93 (1.68-2.20)

      53 (45.5-61.8) to 47.8 (41.2-55.5)
      4.6 (4.2-4.9) to 4.3 (3.9-4.7)211 (196-228) to 208 (190-227)-
      Control585 (541-633) to 525 (489-564)2.46 (2.22-2.72) to 2.24 (2.03-2.47)

      63.1 (54.8-72.7) to 47.8 (41.2-55.5)
      4.7 (4.3-5.2) to 4.6 (4.2-5.0)223 (204-243) to 218 (199-239)-
      Yoo et al.

      2010

      South Korea
      Mean (SD)---pg/mL-
      PA---200 (100) to 100 (100)-
      Control---100 (100) to 100 (100)-
      Resistance Training
      Copeland et al.

      2004

      Canada
      Mean (SD)-DHEA (nmol/l)-pg/mL†-
      PA-26 (13) to 35 (21)

      *within group
      -260 (115) to 260 (115)-
      Control-35 (15) to 34 (15)-231 (173) to 231 (115)-
      Figueroa et al.

      2003

      USA
      Mean (SD)NS----
      Nunes et al.

      2019

      Brazil
      Mean (CI); Δ%-DHEA-S (ug/dL)-pg/mL†-
      Low (3 sets)-35.7 (25.9-45.4) to 34.4 (25.4-43.3); +0.1%-270 (110-420) to 290 (160-430);-
      High (6 sets)-69.2 (39.7-98.7) to 65.5 (38.5-92.6); -4.5%-470 (320-620) to 350 (150-550)-
      Control-53.7 (35.5-71.9) to 51.1 (31.6-70.6); -6.7%-440 (110-770) to 290 (160-430)-
      Orsatti et al.

      2008

      Brazil
      Mean (SD)---pg/mL†-
      PA---231 (66) to 248 (82)-
      Control---269 (154) to 318 (21)-
      Son et al.

      2020

      South Korea
      Mean (SD)-DHEA-S (ug/dL)---
      PA-81.6 (34.9) to 91.1 (40.2)

      *vs. control

      *within group
      ---
      Control-81.0 (35) to 90.1 (35.6)---
      Ward et al.

      2020

      Sweden
      Median (IQR)---pg/mL†nmol/L
      PA---700 (200) to 800 (200)

      *within group
      72.8 (40.0) to 84.5 (33.9)

      *vs. control

      *within group
      Control---800 (300) to 800 (300)81.1 (42.5) to 76.8 (45.8)
      Combined Aerobic and Resistance Training
      Gonzalo‐Encabo et al.

      2020

      Spain
      Δ%-DHEA-S---
      Endurance (aerobic)--13%

      **within group
      -41%

      **vs. concurrent
      -40%

      **vs. concurrent
      NS
      Concurrent (aerobic/resistance)--7.5%+21%+25%NS
      ControlNSNSNSNS
      Monninkhof et al.

      2009

      Netherlands
      Geometric mean; Δ%pg/mL-pg/mLpg/mLnmol/L
      PA1146 to 1097; -2.7%-8.7 to 8.5; -2.9%528 to 508; -3.8%33.9 to 33.6; -0.7%
      Control1172 to 1199; +2.3%-8.7 to 8.5; -1.8%535 to 548; -1.6%34.7 to 33.6; -3.3%
      van Gemert et al.

      2015

      Netherlands
      Geometric mean; Δ%pg/mL-pg/mLpg/mLnmol/L
      PA573 to 488; -14.7-2.4 to 2.0; -17.7%

      *vs. diet

      ***vs. control
      186 to 172; -7.6%49 to 59; +19%

      ***vs. control
      Diet562 to 537; -4.5%2.5 to 2.3; -11.2%197 to 189; -3.7%51 to 57; +13%

      ***vs. control
      Control575 to 560; -2.6%-2.7 to 2.6; -3.9%194 to 186; -4.1%44 to 44; -0.3%
      CI, confident interval; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone-sulfate; IQR, interquartile range; min, minutes; NS, not significant; PA, physical activity; SD, standard deviation; SHBG, sex hormone binding globulin; USA, United States of America; wk, week. *p<0.05, **p<0.01, ***p<0.001. Data was extracted as it was reported in the original manuscript. In some cases, values were converted to the most frequently reported unit to facilitate comparisons between the same hormone, not across hormones, as indicated by †. If available, percent change was reported.

      Physical activity and DHEA, DHEA-S

      The effect of PA interventions on DHEA (n=2 studies
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ) and DHEA-S (n=4 studies
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      ,
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      ) appears limited across the reviewed literature (see Table 2). One study reported no change in DHEA when implementing aerobic PA
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      , whereas another showed significant increases in DHEA following resistance training when compared to baseline.
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      Notably, the sample size was smaller (n=855 vs. n=8761) and the duration of intervention was shorter (n=12 weeks
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      vs. n=12 months
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ) in the latter investigation.
      The changes in DHEA-S following PA programs were variable. Non-significant changes in DHEA-S were reported in various modalities and durations of PA. Following resistance training, (three, 60-minute sessions per week at 80% 1 RM [repetition maximum]), DHEA-S increased (+11.2%, p<0.05) over 12 weeks.
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      However, following 12 weeks of aerobic training (three, 60-minute sessions per week at 75% 1RM), DHEA-S decreased when compared to a combined aerobic and resistance training group (-13%, p<0.01).
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      DHEA-S may be influenced by PA interventions; however, the most effective modality of PA and direction of change is unclear.

      Physical activity and testosterone

      Testosterone was the most widely studied androgen, reported as free (unbound to SHBG) (n=6 studies
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      ) or total (free and bound) (n=11 studies
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      ,
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      • Ward L.J.
      • Nilsson S.
      • Hammar M.
      • et al.
      Resistance training decreases plasma levels of adipokines in postmenopausal women.
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      ) serum concentrations (see Table 2). Most studies reported non-significant changes in total testosterone concentrations following PA interventions when compared to control conditions.
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      ,
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      All of the interventions included a supervised component and ranged from 12 weeks
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      ,
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      to 12 months in duration.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      The studies that reported significant findings had variable results. Gonzalo-Encabo et al. reported that 12 weeks of aerobic exercise (55-75% heart rate reserve [HRR]) reduced total testosterone (-40%, p<0.05) while a combination of aerobic and resistance training (65% 1RM) increased total testosterone (+25%, p<0.01).
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      Ward et al. showed an increase in total testosterone over 15 weeks of a resistance training program.
      • Ward L.J.
      • Nilsson S.
      • Hammar M.
      • et al.
      Resistance training decreases plasma levels of adipokines in postmenopausal women.
      In an aerobic PA and diet group (i.e. caloric restriction, participants ingested between 1,200-2,000 cal/day based on baseline weight), significant reductions in testosterone were observed when compared to controls.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      Resistance training may modestly increase, and aerobic exercise modestly decrease total testosterone, but factors such as diet may impact the strength of this association.
      Unlike total testosterone, all studies reported reductions in free testosterone concentrations among female exercisers.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      However, some findings became insignificant for studies which adjusted for changes in fat loss, implying that reductions in adiposity enhanced the effects of the PA intervention on free testosterone.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      Significant reductions in free testosterone were observed in females engaging in aerobic PA (-41%), but not in combined aerobic and resistance training (+21%) (between group difference: p<0.01).
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      Findings from aerobic interventions over 12 months revealed reductions in free testosterone only in females who accumulated more than 225 min/wk of aerobic PA (70-80% HRR), when compared to less than 225 min/wk.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      Compared to calorie-restriction alone, significantly greater decreases in free testosterone followed aerobic PA
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      and a combination of aerobic and resistance PA (TER: 0.92, 95% CI 0.85 to 0.99).
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      No studies that implemented a resistance program measured changes in free testosterone. Aerobic PA may reduce free testosterone concentrations more so than diet alone, especially when performed for longer durations per week. Further, changes in body composition induced by regular PA may be an important mechanism responsible for changes in androgen concentrations.

      Physical activity and SHBG

      A total of 8 studies measured SHBG concentrations (see Table 2).
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      ,
      • Ward L.J.
      • Nilsson S.
      • Hammar M.
      • et al.
      Resistance training decreases plasma levels of adipokines in postmenopausal women.
      Postmenopausal females participating in aerobic PA for 30 to 60 minutes, 3 to 5 days per week demonstrated significant increases in SHBG when compared to controls.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      Greater increases in SHBG were detected in the combined aerobic PA and diet group over 12 months when compared to PA, diet, or control conditions alone (i.e. PA + diet = +25.8%, PA = -0.7%, diet = +22.4%, control = -2.7%).
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      Significant increases in SHBG were observed in those participating in combined aerobic and resistance PA when compared to controls (p<0.001).
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      Greater increases in SHBG were seen in females who exercised more than 225 minutes/week when compared to those who exercised less than 150 minutes/week (p<0.001).
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      However, these findings were no longer significant (p=0.29) when adjusting for body mass change over 12 months,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      and there was no significant increase in SHBG concentrations in the aerobic PA group that exercised 300 min/wk when compared to 150 min/wk.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      No changes were reported with resistance training over 1567 weeks or in combined aerobic/resistance training over 12 weeks
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      or 12 months.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      These findings suggest that aerobic PA increases SHBG concentrations, potentially to a greater extent than diet alone; the dose of PA and its relationship with resistance training needs further clarification.

      Follow up trials

      In a 30-month follow up study to the Campbell et al.’s 2012 RCT,
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      significantly greater increases in SHBG (+80.5%) were observed in females who were randomized to the 12-month aerobic PA and caloric restriction intervention when compared to those in the control group (+80.5% vs. +47.9%; p<0.001).
      • Duggan C.
      • Tapsoba JdD.
      • Stanczyk F.
      • Wang C.-Y.
      • Schubert K.F.
      • McTiernan A.
      Long-term weight loss maintenance, sex steroid hormones, and sex hormone-binding globulin.
      The original decrease in free testosterone in the aerobic PA and caloric restriction group was lost at 30 months;
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      no significant changes in total or free testosterone were observed in any group at 30 months.
      • Duggan C.
      • Tapsoba JdD.
      • Stanczyk F.
      • Wang C.-Y.
      • Schubert K.F.
      • McTiernan A.
      Long-term weight loss maintenance, sex steroid hormones, and sex hormone-binding globulin.
      Unfortunately, this study did not report on the long-term PA levels of these females. In Friedenreich et al.’s 24-month follow up
      • Friedenreich C.M.
      • Wang Q.
      • Yasui Y.
      • et al.
      Long-term effects of moderate versus high durations of aerobic exercise on biomarkers of breast cancer risk: follow-up to a randomized controlled trial.
      to the Breast Cancer and Exercise Trial in Alberta (BETA) trial,
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      SHBG significantly decreased (42.9 to 40.6 nmol/L) in the moderate aerobic PA groups follow-up
      • Friedenreich C.M.
      • Wang Q.
      • Yasui Y.
      • et al.
      Long-term effects of moderate versus high durations of aerobic exercise on biomarkers of breast cancer risk: follow-up to a randomized controlled trial.
      when compared to the original significant increase (42.9 to 46.7nmol/L) observed at 12 months (p<0.001).
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      Changes in androgens may reverse with the cessation of PA. This emphasizes the importance of long-term regular PA in addition to fat loss achieved through caloric restriction for androgen maintenance.

      Physical activity and CVD risk factors

      CVD risk factors reported in the reviewed studies were scarce and inconsistent. The influence of anthropometric changes (i.e. BMI, body mass or body fat) on androgens following PA were the most frequently examined parameters.
      • Figueroa A.
      • Going S.
      • Milliken L.
      • et al.
      Effects of Exercise Training and Hormone Replacement Therapy on Lean and Fat Mass in Postmenopausal Women.
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      ,
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      ,
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      Table 3 summarizes the changes in cardiovascular health indicators following the PA interventions.
      Table 3Changes in Cardiovascular disease risk factors data at from baseline and to follow up after a physical activity intervention.
      GroupBMI (kg/m2) or Body Mass (kg)Body Fat (%)Systolic BP (mmHg)Cardiorespiratory fitness†Fasting Insulin (μU/mL) or IGF-1 (ng/mL)Cortisol (nmol/L)
      Aerobic Activity
      Campbell et al.

      2012

      USA
      Insulin
      PA83.7 (12.3) to 80.9 (12.2) kg; -3.3%

      *vs. control

      ***vs. diet

      ***vs. PA + diet
      47.3 (4.1) to 45.5 (5.0) %; -3.8%

      ***vs. control

      ***vs. diet

      ***vs. PA + diet
      -1.9 (0.3) to 2.0 (0.4) L/min; +10.1%

      ***vs. control

      ***vs. diet
      10.9 (10.0-12.0) to 10.1 (9.1-11.0) μU/mL; -8.2%

      **vs. diet

      ***vs. PA + diet
      -
      Diet84 (11.8) to 74.9 (12.3) kg; -10.8%

      ***vs. control
      47 (4.3) to 42.1 (6.4)%; -10.6%

      ***vs. control

      ***vs. PA + diet
      -1.9 (0.3) to 1.8 (0.3)L/min; -2.3%

      ***vs. PA + diet
      11 (9.8-12.2) to 8.1 (7.3 to 9) μU/mL; -26.1%

      ***vs. control
      -
      PA + diet82.5 (10.8) to 72.7 (10.9) kg; -11.9%

      ***vs. control
      47.4 (4.5) to 41.1 (7.0) %; -13.4%

      ***vs. control
      -1.9 (0.3) to 2.1 (0.4) L/min; +7.6%

      ***vs. control
      10.7 (9.7-11.8) to 7.9 (7.1-8.7) μU/mL; -26.5%

      ***vs. control
      -
      Control84.2 (12.5) to 83.7 (12.3) kg; -0.6%47.3 (4.4) to 47.2 (5.3) %; -0.5%-1.9 (0.4) to 1.9 (0.3) L/min; -0.9%12.0 (10.8-13.3) to 11.6 (10.4-12.9) μU/mL; -3.7%-
      Friedenreich et al.

      2010

      Canada
      PAΔ -2.3 (2.9-1.7) kg

      ***vs. control
      --Δ +3.9 (2.8-4.9) mL/ kg/min

      ** vs. control
      --
      ControlΔ 0.5 (1.0-0.1) kg--Δ +0.7 (-0.2 to 1.6) mL/ kg/min--
      Friedenreich et al.

      2015

      Canada
      Moderate (150min/wk PA)Δ -1.9 (2.4-1.3) kgΔ -1.1 (1.5-0.7) %-Δ +4.0 (3.3-4.8) mL/ kg/min--
      High (300min/wk PA)Δ -2.6 (3.2-1.9) kgΔ -2.0 (2.5-1.5) %

      **vs. moderate group
      -Δ +5.0 (4.2-5.9) mL/ kg/min--
      Kim & Kim, 2012

      South Korea

      Insulin
      PA25.0 (1.3) to 24.2(1.2) kg/m2

      ***vs. control

      **within group
      36.0 (3.0) to 33.5 (3.3) %

      ***vs. control

      **within group
      133 (5) to 125 (5)

      *** vs. control ***within group
      -8.2 (1.0) 7.3(1.0) μU/mL **vs. control ***within group-
      Control25.1 (1.5) to 25.9(1.4) kg/m2 **within group36.6 (1.7) to 37.5 (2.4) %

      **within group
      132 (4) to 134 (3)

      **within group
      -8.1 (1.2) to 8.4(1.2) μU/mL

      ***within group
      -
      McTiernan et al.

      2004

      USA
      -------
      Yoo et al.

      2010

      South Korea
      PABMI

      26.6 (2.9) to 26.3 (3.1) kg/m2

      Body Mass

      63.9 (7.8) to 62.9 (8) kg
      -135 (8) to 130 (10)---
      ControlBMI

      25.4 (3.0) to 25.1 (3.0) kg/m2

      Body Mass

      59 (9.7) to 58.6 (10.1) kg
      -128 (14) to 125 (15)---
      Resistance Training
      Copeland et al.

      2004

      Canada
      IGF-1
      PA25.7 (2.7) to 25.6 (2.6) kg/m239.9 (2.6) to 40.4 (2.8) %--220 (175) to 203 (158) ng/mL

      **vs. control
      401 (154) to 392 (120) nmol/L

      ** within group
      Control31.6 (7.6) to 31.6 (7.7) kg/m241.1 (5.5) to 40.9 (4.9) %--110 (33) to 109 (42) ng/mL406 (121) to 383 (102) nmol/L
      Figueroa et al. 2003

      USA
      PA-Δ -0.9 %

      * within group
      --NRNR
      Control-Δ +1.0 %
      Nunes et al. 2019

      Brazil
      IGF-1
      Low (3 sets)----114 (85-142) to 122 (81-163) ng/mL; +6.7%482 (328-639) to 630 (450-811) nmol/L; +73%
      High (6 sets)----134 (111-157) to 142 (114-171) ng/mL; +7.3%518 (391-646) to 611 (442-779) nmol/L; +36.8%
      Control----138 (104-172) to 135 (101-169) ng/mL; +4.1%451 (292-610) to 543 (263-823) nmol/L; +16.8%
      Orsatti et al. 2008

      Brazil
      IGF-1
      PA28.8 (4.5) to 29.4 (4.8) kg/m235.6 (8.1) to 34.9 (8.3) %149 (71) to 205 (82) ng/mL

      **vs. control *within group
      433 (124) to 447 (163) nmol/L
      Control27.6 (5.1) to 27.1 (5.1) kg/m232.6 (7.8) to 31.5 (7.8) %129 (45) to 113 (53) ng/mL339 (127) to 356 (127) nmol/L
      Son et al. 2020

      South Korea
      IGF-1
      PA26.5 (1.0) to 26.0 (0.9) kg/m2

      *vs. control

      *within group
      35.6 (2.9) to 34.0 (3.0) %

      *vs. control *within group
      139 (3) to 136 (4)

      *vs. control *within group
      -145 (19) to 151 (18) ng/mL

      * vs. control

      *within group
      -
      Control26.9 (1.0) to 26.8 (1.1) kg/m235.8 (3.2) to 36.1 (2.9) %138 (5) to 138 (4)-144 (15) to 140 (15) ng/mL-
      Ward et al. 2020

      Sweden
      PA28.1 (3.8) to 27.9 (3.9) kg/m2-----
      Control26.7 (3.6) to 26.8 (3.8) kg/m2
      Combined Aerobic and Resistance Training
      Gonzalo‐Encabo et al. 2020

      Spain
      Endurance (aerobic)Δ -1.9 %

      *vs. control
      --Δ +13%

      ** within group
      -Δ -17.5%

      * within group
      Concurrent (aerobic/ resistance)Δ -1.4 %

      *vs. control
      --Δ +12%

      ***within group
      -NR
      ControlΔ -1.0 %--NR-NR
      Monninkhof et al.

      2009

      Netherlands
      PA-39.8 to 38.9 %; -2.2%----
      Control-40.9 to 40.9 %; 0%----
      van Gemert et al.

      2015

      Netherlands
      PA29.0 to 27.0 kg/m2; -6.8%

      ***vs. control
      43.9 to 39.8 %; -9.3%

      ***vs. control

      ***vs. diet
      -1.8 to 1.9 L/min; +6.7%

      **vs. control

      ***vs. diet
      --
      Diet29.2 to 27.5; -6.1%

      ***vs. control
      44 to 41.5%; -5.7%

      ***vs. control
      -1.7 to 1.7L/min; -2.5%--
      Control29.3 to 29.4 kg/m2; +0.1%43.5 to 43.7 %; +0.5%-1.8 to 1.7 L/min; -4.5%--
      BMI, body mass index; BP, blood pressure; IGF-1, insulin-like growth factor-1; min, minutes; NR, not reported; PA, physical activity; USA, United States of America; wk, week;
      Data presented as mean (95% CI or standard deviation); *P<0.05, **P<0.01, ***P<0.001
      †Insulin was analyzed although only 2 studies reported on it given the well-established relationship between androgens and insulin

      Physical activity and body composition

      Almost all aerobic PA,
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      and combined aerobic and resistance
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      programs showed significant decreases in BMI and or body fat. Few resistance programs influenced BMI
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      or body fat.
      • Figueroa A.
      • Going S.
      • Milliken L.
      • et al.
      Effects of Exercise Training and Hormone Replacement Therapy on Lean and Fat Mass in Postmenopausal Women.
      ,
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      The only aerobic program that did not yield significant decreases in BMI or body fat had the lowest exercise intensity (60% HRR).
      • Yoo E.J.
      • Jun T.W.
      • Hawkins S.A.
      The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women.
      Inconsistencies were observed regarding the role of body composition in mediating the effects of PA on DHEA-S concentrations. Son et al. showed a moderate, negative correlation between the change in % body fat and DHEA-S concentrations (r=-0.4, p<0.05) following a 12-week resistance-band PA program.
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      Gonzalo-Encabo et al. found a significant increase in SHBG (+21%) and decrease in DHEA-S (-13%) (p<0.05) in females who lost more than 2 kg of fat mass in a combined aerobic and resistance program.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      Of note, among participants who lost more than 2% of body fat, those participating in a 12-month moderate-intensity aerobic PA program when compared to control stretching experienced greater reductions in androstenedione (-17% vs. -9%), DHEA (-20% vs. -8%) and DHEA-S (-22% vs. 3%), although no statistical significance was reached.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      Future research should explore whether PA participation may, thus, enhance reductions in androstenedione, DHEA, and DHEA-S concentrations independent of changes in body composition.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      No other studies reported on this relationship, rendering it challenging to draw conclusions.
      Changes in testosterone following PA were more pronounced in participants who lost body fat or body mass.
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      In females who lost more than 2% body fat, an aerobic PA program significantly reduced total testosterone at 3 (PA: -10%, control: -1.6%, p<0.005) and 12 (PA: -8%, control: -3.6%, p<0.02) months when compared to controls (p<0.001).
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      Similarly, following 4 months of combined aerobic and resistance training, the reductions in total testosterone were significant in females who lost more than 2% body fat (PA: -12.9%, control: +0.2%, p=0.005), but not in the whole sample of participants (PA: -3.8%, control: +2.4% p=0.14).
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      Both of these studies had similar sample sizes (n=87 and n=96, respectively), target intensity (moderate-to-vigorous PA), and incorporated aerobic training into the intervention.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      Further, significant decreases in free testosterone were detected in those participating in 12 months of aerobic exercise and who lost more than 2% of their body fat when compared to controls.
      • McTiernan A.
      • Tworoger S.S.
      • Rajan K.B.
      • et al.
      Effect of exercise on serum androgens in postmenopausal aomen: a 12-Month randomized clinical trial.
      ,
      • Monninkhof E.M.
      • Velthuis M.J.
      • Peeters P.H.
      • Twisk J.W.
      • Schuit A.J.
      Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial.
      Decreases in body mass, body fat, and waist circumference were significantly associated with increases in SHBG following aerobic PA (p<0.05).56 57, 60 For instance, regardless of the minutes of aerobic PA per week (150 vs. 250 min/wk), decreases in body mass were associated with increases in SHBG (r=-0.29, p<0.0001).
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      Greater decreases in free testosterone and increase in SHBG (p<0.001) were observed following aerobic PA and caloric restriction when compared to aerobic PA alone.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      These findings suggest that fat loss achieved through exercise strengthens the association between free, total testosterone, and SHBG, and PA.

      Physical activity and other cardiovascular health indicators

      Other CVD health indicators examined included CRF, systolic blood pressure, fasting insulin, insulin-like growth factor (IGF-1) and cortisol. The included studies reported significant improvements in CRF following all types of PA interventions when compared to controls.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      ,
      • Friedenreich C.M.
      • Woolcott C.G.
      • McTiernan A.
      • et al.
      Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
      ,
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      ,
      • van Gemert W.A.
      • Schuit A.J.
      • van der Palen J.
      • et al.
      Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial.
      Friedenreich et al. found that improvements in CRF were positively correlated with increases in SHBG (rs=0.11, p<0.04);
      • Friedenreich C.M.
      • Neilson H.K.
      • Wang Q.
      • et al.
      Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial.
      no other significant associations between CRF and androgens were reported.
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      Systolic blood pressure was rarely measured; this may be due to sampling bias inherent in the included RCTs which enrolled predominantly healthy females. Small reductions of 3 to 8 mmHg were reported in systolic blood pressure following several PA programs.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      ,
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      Blood biomarkers including fasting insulin, insulin-like growth factor (IGF-1) and cortisol were measured in several studies, likely due to evidence showing their bi-directional relationship with androgens.
      • Baptiste C.G.
      • Battista M.-C.
      • Trottier A.
      • Baillargeon J.-P.
      Insulin and hyperandrogenism in women with polycystic ovary syndrome.
      A combination of PA and caloric restriction enhanced the reductions in fasting insulin (PA only: -8%, PA + diet: -27%).
      • Campbell K.L.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • et al.
      Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial.
      Kim and Kim showed that fasting insulin decreased following aerobic PA, yet increased in the control group.
      • Kim J.W.
      • Kim D.Y.
      Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women.
      Following PA, inconsistent findings were observed for IGF-1 and cortisol. PA interventions decreased,
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      increased,
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      ,
      • Son W.M.
      • Pekas E.J.
      • Park S.Y.
      Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.
      or showed no significant changes in IGF-1.
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      Similarly, two studies of different PA modalities reported decreases in cortisol (combined aerobic and resistance
      • Gonzalo-Encabo P.
      • Valadés D.
      • García-Honduvilla N.
      • de Cos Blanco A.
      • Friedenreich C.M.
      • Pérez-López A.
      Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
      vs. resistance only
      • Copeland J.L.
      • Tremblay M.S.
      Effect of HRT on hormone responses to resistance exercise in post-menopausal women.
      ) whereas two reported no changes.
      • Nunes P.R.P.
      • Barcelos L.C.
      • Oliveira A.A.
      • et al.
      Muscular strength adaptations and hormonal responses after two different multiple-set protocols of resistance training in postmenopausal women.
      ,
      • Orsatti F.L.
      • Nahas E.A.P.
      • Maesta N.
      • Nahas-Neto J.
      • Burini R.C.
      Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women.
      No studies directly examined the associations between insulin, IGF-1 or cortisol, and androgens.

      DISCUSSION

      Summary of findings
      This review explored the relationship between PA, androgen concentrations, and cardiovascular health indicators in postmenopausal females. The influence of PA on androgens was varied. Trends across studies demonstrated no changes in androstenedione concentrations and conflicting data for DHEA and DHEA-S. The direction of change in total testosterone appeared to depend on the type of PA implemented, with some reductions following aerobic PA programs and some increases following resistance training. Reductions in free testosterone followed most aerobic PA programs. Nearly all studies reported an increase in SHBG following a PA program, regardless of the type of PA. A combination of diet and/or fat loss enhanced the influence of PA interventions on DHEA-S, free and total testosterone, and SHBG concentrations; high-intensity aerobic PA interventions had the greatest influence on body composition.
      The association between cardiovascular health indicators and changes in androgen concentrations following PA interventions was sparsely reported and conflicting. This limited our ability to discuss the potential mechanisms underpinning androgens and cardiovascular health indicators following PA in postmenopausal females. Amongst all PA modalities, there were modest reductions in total body and fat mass and BMI, increases in CRF, and inconsistent findings regarding IGF-1 and cortisol changes. Systolic blood pressure was rarely measured, and fasting insulin decreased in response to combined PA and diet interventions. The mechanisms that mediate the decrease in testosterone concentrations following aerobic training and the increase following resistance training should be further explored. Physiological changes related to increases in lean body mass and decreases in body fat may play a role.
      • Marx J.O.
      • Ratamess N.A.
      • Nindl B.C.
      • et al.
      Low-volume circuit versus high-volume periodized resistance training in women.
      It is possible that the relationship between PA and androgens and PA and CVD exist independent of each other, but both are impacted by PA and weight loss. Females who are normal or underweight may have less opportunity for sex hormone improvements as the degree of change may depend on the amount of fat mass lost. However, if the effect of fat loss from caloric restriction and PA are similar, exercise would be recommended as the preferred treatment to avoid a decrease in muscle mass while simultaneously improving cardiovascular risk factors in postmenopausal females.

      Strengths and limitations

      Merits of our study included the use of evidence from RCTs, the highest quality of evidence, a robust search, and the inclusion of all androgens and traditional cardiovascular health indicators. This review also incorporated androgen concentrations adjusted for changes in BMI and or fat loss, where appropriate, to investigate the complex relationship between adiposity, androgens, and SHBG. Limitations included a lack of homogeneity in reported androgen concentrations and cardiovascular health indicators among previous literature, limiting a more comprehensive analysis. The relationship between changes in the ratio of estrogen to testosterone concentrations following PA was not reported in the included studies, thus excluded from our review. We also did not report on cardiovascular health indicators that were not present in over 3 studies (e.g. waist circumference). Such additions may provide further insight into the association between androgens and cardiovascular health in postmenopausal females.

      Future directions

      The results of this review were heterogenous with regards to sample sizes, androgens included, units of androgens used for analysis, and the frequency, duration, modality, and intensity of PA interventions. Most studies did not report similar cardiovascular health indicators or adjust for changes in adiposity, which is needed in future research. Specific suggestions for developing literature in this field include conducting RCTs with larger sample sizes of postmenopausal females to evaluate changes in androgens in participants with various BMI and PA levels and differing health status. We recommend that future PA research includes a comprehensive panel of all endogenous serum androgens and SHBG to standardize the evaluation and interpretation of the role of PA in modulating androgens and cardiovascular health. There is no defined ‘high’ or ‘low’ physiologic androgen range in postmenopausal females, so future studies should aim to define this level to create a baseline value.
      • Davison S.L.
      • Bell R.
      • Donath S.
      • Montalto J.G.
      • Davis S.R.
      Androgen levels in adult females: changes with age, menopause, and oophorectomy.
      Moreover, studies should explore changes in FAI, androstenediol, and dihydrotestosterone as these were not reported in the included trials and, thus, could not be examined. RCTs comparing diverse PA modalities (e.g. yoga, walking, endurance training, resistance training), intensities (e.g. low, moderate and vigorous), and durations are necessary to delineate the most effective PA intervention in modulating the androgen environment. When exploring the relationship between androgens and PA, studies should investigate how cardiovascular health indicators impact this association and adjust for changes in BMI and or fat loss to explore the relative impact of adiposity and SHBG on resulting changes in androgen concentrations.

      CONCLUSION

      Our review has shown that PA interventions may alter some androgen (free and total testosterone, SHBG) concentrations in postmenopausal females. Fat loss influences the effect of PA on androgens, however the synergistic role of PA and androgens on cardiovascular health merits further examination. Evidence exploring the relationship between changes in androgens and cardiovascular health indicators was scarce and inconsistent. More research is needed to clarify the relationships between CVD, PA, and androgens in postmenopausal females. Future studies should focus on incorporating cardiovascular health indicators, standardizing the measurement of androgens to allow for direct comparison, including more diverse PA modalities, and accounting for the role of adiposity in androgens, PA, and cardiovascular health.

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      • Clarke J.
      • Colley R.
      • Janssen I.
      • Tremblay M.S.
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      Acknowledgements

      We would like to acknowledge Laura Salisbury for the creation of our graphical abstraction.
      Data availability: All available data is provided in the Tables and Figures.

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