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Women, Hormones, Metabolism & Energy Expenditure
Len Kravitz, Ph.D., Afton Cazares, M.A., Christine Mermier, Ph.D.

Introduction
During endurance exercise, fuel source and utilization plays a primary role in performance. The contribution and expenditure of fat and carbohydrates for the synthesis of ATP during exercise is regulated by several factors, including duration of exercise, intensity of work, a person's age, training status, diet and gender. Proteins contribute a minor 1-8% of the fuel needs during submaximal exercise (Isacco, Duché and Boisseau, 2010). Before puberty, there is no difference between males and females when it comes to substrate usage during exercise (Isacco, Duché and Boisseau). This is not the case during adulthood, since women are known to rely more on fat than men for the same relative intensity of exercise._Further exploration of the physiological characteristics in metabolism, energy expenditure and hormonal influences on women during exercise follow.

Hormones 101: Altering Cell Function through Feedback Circuits
The endocrine, meaning hormone secreting, system is a bodily network of tissues and organs that involve the release of specialized molecules known as hormones. The word hormone comes from the Greek root meaning 'impetus'. Hormones are chemical messengers released from one or more cells that send signals (via the blood) to other cells in various parts of the body. Cells respond to a hormone if they have a specific receptor for that hormone. The hormone binds to the receptor protein, resulting in the activation of a signal mechanism in the cell that leads to responses that alter its growth, function or metabolism. Feedback circuits are the major control mechanisms of the endocrine system. Negative feedback is much more common, although positive feedback circuits do occur in humans. The heating system in a home is a straightforward analogy how a negative feedback circuit works. When the furnace produces enough heat to elevate temperature above the set point of the thermostat, the thermostat is triggered and turns off the furnace. Thus, heat is feeding back 'negatively' on the source of heat. When temperature drops back below the set point, negative feedback is gone, and the furnace comes back on.

Introducing the Major Female Hormones and Their Functions
Two major female sex hormones, estrogen and progesterone play an essential role in a women's reproductive system. Estrogen and progesterone, which are derived from cholesterol, are often referred to as ovarian hormones since they are produced and secreted primarily by the ovaries (D'eon and Braun, 2002). Estrogen, which is also secreted to a lesser extent by the adrenal glands, actually refers to a class of 18-carbon steroid hormones. A steroid hormone effects growth and development of sex organs. The most biologically active estrogen is 17_-estradiol or estradiol. Estrone and estriol are also estrogens, but less biologically active than estradiol (D'eon and Braun, 2002). McCarthy notes that estradiol is at is highest level in the brain prenatally, or during the first few days of life, thus suggesting it has potent and wide-ranging effects on the developing brain. Hormones from the hypothalamus and pituitary gland regulate and control the release of estrogen and progesterone.

Overview of Metabolism
Metabolism is the sum total of all chemical reactions involved in sustaining the life of a cell, and thus the organism. It can be divided into two categories: catabolism or the break down of molecules to obtain energy and anabolism, which is the synthesis of compounds needed by the cells. Carbohydrates, proteins and fats provide a variety of substances that are essential for the building, upkeep, and repair of body tissues, and for the efficient functioning of the body. Carbohydrates are provided in three forms: starch, sugar, and cellulose. Starch and sugar are essential sources of energy for humans. Cellulose is an indigestible carbohydrate known as dietary fiber that provides volume or bulk in food that has no caloric value. For this reason, cellulose has become a popular bulking agent in diet foods. Protein is the chief tissue builder of every cell in the body. Proteins help to make hemoglobin in the blood that carries oxygen to the cells, form anti-bodies that fight infection and supply nitrogen for DNA and RNA genetic material. Fats are concentrated sources of energy because they provide twice as much energy as either carbohydrates or protein. Fats function to make up part of the structure of cells, form a protective cushion and heat insulation around vital organs, carry fat soluble vitamins and provide a reserve storage for energy.

Energy Regulation, Hormonal Influences and Carbohydrate Metabolism
A major role of carbohydrate metabolism during a resting state is to maintain a constant supply of glucose to the brain. Carbohydarate in the form of glucose traveling in the bloodstream is the fuel that powers the brain. Glucose is the only fuel normally used by brain cells. Neurons, the cells that send bioelectric messages to one another, have a large demand for glucose because they're always in a state of metabolic activity. Even during sleep, neurons are still at work repairing and rebuilding their structural components. Because neurons cannot store glucose, they depend on a constant supply of this precious fuel. From a health standpoint, repeatedly overloading the bloodstream with sugar (such as from drinking too many soft drinks) places an additional load on the pancreas to continually have to secrete more insulin, called hyperinsulimia, which may lead to insulin resistance (Alemany, 2011). Insulin resistance is a condition in which normal amounts of insulin are inadequate in transferring blood glucose into cells, which progressively increases the risk of type 2 diabetes.

The rate and amount of carbohydrate (via glucose and glycogen) during rest and exercise is primarily determined by the energy needs of the muscle. Blood glucose and muscle glycogen are essential for vigorous and prolonged strenuous exercise. Exhaustion during exercise is highly influenced by the development of hypoglycemia (low blood glucose) and depletion of muscle glycogen.

In respect to female utilization of glucose and glycogen during endurance exercise, the consensus in the research suggests there is a lower glucose appearance and slower rate of glucose disappearance in women, as compared with men during endurance exercise (Tarnopolosky 2008). Tarnopolosky, in his research review, summarizes that the research indicates this may be a result of a lower sympathetic (nervous system responsible for the fight-or-flight response) nervous activation in women, and not due to the ovarian hormones. Tarnopolosky continues that slightly inhibited carbohydrate utilization during endurance exercise observed with women is also reflective of hormonal influences affecting fat metabolism.

Circulating glucose is the primary fuel for the brain. With excess sugar intake, the pancreas secretes higher insulin levels, which promotes the unused glucose by muscle and liver to be stored in adipose tissue. During exercise glucose enters the muscle via insulin-induced or contraction-induced GLUT-4 translocator proteins. Glycogen, the stored form of glucose in the liver and muscle, and glucose (from the blood), breakdown via a series of metabolic steps (called glycogenolysis and glycolysis, respectively) to appreciably contribute muscle fuel (in the form of ATP) during vigorous exercise. Lactate, a byproduct of carbohydrate metabolism during strenuous exercise is sent to the liver where it is converted back to glucose (called gluconeogenesis) via a pathway called the Cori cyle.

Energy Regulation, Hormonal Influences and Fat Metabolism
An overview of the regulation of fat oxidation is provided in Focus Box 2. The exercise intensity is the primary factor determining the degree of fat or carbohydrate utilization during exercise. During very light exercise most of energy fuel in the form of ATP is being derived from fat. However, as the exercise intensity increases, fat oxidation increases until exercise intensities of about 65% VO2max (Jeukendrup, 2002). Jeukendrup notes that a gradual decline in the rate of fat oxidation is observed beyond this intensity until an exercise intensity of >80% VO2max, where fat oxidation declines rapidly. However, with training this drop of fat utilization is less (in women and men), thus demonstrating that with continual endurance training the body is more efficient at utilizing fat as a fuel.
Tarnopolosky (2008) notes that most studies show that females store slightly higher levels of intramuscular fat, which is stored in small lipid droplets in muscle. Tarnopolosky continues that women have more lipid droplets as opposed to larger lipid storage depots. During moderately vigorous exercise that is sustainable for 90 minutes or longer (approximately 55% to 75% VO2max) there is a progressive decline in muscle glycogen usage and greater reliance on fat oxidation (breakdown) for ATP synthesis (Holloszy et al., 1998). This adaptation during endurance exercise is often referred to as glycogen sparing. Most research indicates that total body lipolysis (fat breakdown) is higher in women than in men, as glycerol (the backbone molecule of triglycerides) is elevated as compared to men during endurance exercise (Tarnopolosky, 2008; D'Eon and Braun, 2002). Current investigations indicate that women use more fat and less carbohydrate to fuel exercise at any given submaximal intensity due to estradiol (Tarnopolosky). Tarnopolosky adds that current findings indicate women are not as efficient in carbohydrate-loading protocols that result in supercompensation of glycogen storage. This may also be a direct result of higher levels of estradiol (Tarnopolosky). This factor may slightly compromise performance during marathon and ultra marathon-like events in females.

Ingested triglycerides enter the blood stream from the small intestines packaged as chylomicrons or very-low-density lipoproteins. Lipoprotein lipase (in tissues under the capillaries) separates the free fatty acids (FFA) from the glycerol backbone for storage in fat (and some in muscle). Lipolysis is the breakdown of triglycerides into free fatty acids, which are transported by albumin in the blood to muscle. Epinephrine stimulates lipolysis while insulin inhibits it. Specialized protein shuttles (FABP) take FFA into the muscle which can be stored as intramuscular triglycerides (IM-TG). FFA in muscle enter the mitochondria via the enzymes carnitine palmityl transferase 1 and II (CPT-1 and CPT-II) for fat breakdown (oxidation) in the mitochondria and the liberation of ATP for energy.

How Does the Menstrual Cycle Effect Exercise Metabolism?
The ovarian hormones, estrogen and progesterone fluctuate during the menstrual cycle (see Questions and Answers on menstrual cycle) with inferences for exercise performance (Oosthuyse and Bosch, 2010). The authors, in their research review, clarify that some studies show endurance performance is affected by menstrual cycle, while other studies report no difference. Nevertheless the increase in estrogen concentrations relative to progesterone levels during the luteal phase suggests that endurance performance can be readily increased during the mid-luteal phase. In addition, during the late follicular phase, which is characterized by a surge in estrogen and suppression of progesterone, endurance performance is enhanced. Oosthuyse and Bosch summarize that estrogen alters fat, carbohydrate and protein metabolism, favorably affecting performance whereas progesterone appears to act in opposition (to estrogen). The researchers propose that increases in estrogen enhance glucose appearance and utilization by the slow-oxidative type I muscles fibers. The high estrogen content during the luteal phase augments glycogen storage, which additionally has a meaningful affect on exercise performance. Lastly, the authors note that both estrogen and progesterone suppress gluconeogenesis output during exercise. Gluconeogenesis is a metabolic pathway depicted in Focus Box 2 that results in the synthesis of glucose from substrates such as lactate, amino acids and odd-chain fatty acids. It is a primary mechanism the body uses to keep blood glucose levels from dropping too low during sustained exercise bouts. This suggests that during ultra-long endurance events females may have somewhat compromised performance.

What is the Female Hormonal Response to Resistance Training?
Resistance training is essential for the maintenance of musculoskeletal health throughout life. It also decreases the risk of bone deficiencies such as osteopenia (mineral density is lower than normal), osteoporosis and the risk of bone fractures. The risk for decreases in bone density and/or bone mass becomes greater with age, especially in women. According to a review by Kaufman, Reginster, Boonen, et al. (2012), women who have low bone mineral density have a lifetime fracture risk of up to 50 percent as opposed to13 to 25 percent for men. Estrogen, one of the ovarian hormones, is known to play a key role in bone metabolism. Women who are deficient in estrogen tend to have a negative impact in bone turn-over markers and bone mineral density (Moghadasi and Stravaspour, 2012). The implementation of a resistance training program may help increase the hormones of bone formation, especially in women of reproductive age. Women who are postmenopausal have a decrease in estrogen levels, which can lead to negative effects on bone mass (Moghadasi and Stravaspour, 2012). Other hormones effecting bone formation from resistance exercise include growth hormone, insulin, insulin like growth factor I, leptin, and parathyroid hormone.

Moghadasi and Stravaspour investigated the hormonal effects of resistance training with twenty sedentary women, age 25 ± 3.2 years (all having normal menstrual cycles). Throughout the course of 12 weeks, the women participated in a 50 to 60 minute resistance training routine, three days a week. The program included two to four sets (8 to 12 repetitions) of eight exercises which were performed at 65 percent to 85 percent of their 1-repetition max (1RM). Exercises included chest press, leg extension, shoulder press, leg curls, latissimus dorsi pull-down, let press, arm curls and triceps extension. During the follicular phase of the menstrual cycle, hormonal blood profiles were taken prior to the twelve weeks, and after the study was completed. The results indicated significant increases in muscular strength following the 12-week program as well as increases in growth hormone, estrogen, testosterone and parathyroid hormone. The authors concluded that sedentary women who engage in a multi-set total body resistance-training program (similar in design and intensity as the present study) would experience an increase in the hormones of bone formation and other musculoskeletal health benefits.

How Does Menopause Affect Exercise Performance?
The higher utilization of fat as a substrate in women decreases at menopause. This is most likely attributable to a decline in plasma estrogen (and progesterone) concentrations and a drop in fat-free muscle mass (Isacco, Duché and Boisseau, 2010). However, the researchers note that obese, post-menopausal women training at approximately 50% of the aerobic capacity do utilize fat more efficiently as compared to similar-aged men. These results were observed despite similar basal plasma estradiol concentrations in the women and men, and higher plasma free fatty acid levels in men. Thus the increase in plasma estrogen concentrations observed in premenopausal women induced by exercise may still partially occur in postmenopausal obese women. More research is needed in this area to fully explain and understand the mechanisms involved.

Practical Applications
Results from an extensive review of literature show clearly that compared to men, women oxidize more fat and less carbohydrate at various levels of submaximal endurance exercise. This suggests that personal trainers should incorporate a combination of low-to-moderate steady state submaximal cardiovascular endurance and fast continuous maximal steady state training to most effectively promote fat utilization with their female clients. Exercise professionals may also consider alternating interval training at slightly lower work intervals during the high intensity bouts, as this may also promote enhanced fat utilization during the workout. The research also objectively indicates the importance of total body resistance training, as it favorably enhances several hormonal responses and adaptations that impressively improve musculoskeletal health.

Side Bar 1: Ten Questions and Answers
1) What hormonal changes are observed with boys and girls at puberty?
At puberty, girls have more adipose tissue development due to estrogen and boys have more muscle mass development due to testosterone (Isacco, Duché and Boisseau, 2010).
2) What is the menstrual cycle and its distinct phases?
The female human menstrual cycle is a "monthly" cycle that can vary around an average of ~28 days per cycle to prepare for a possible pregnancy. Usually once a month the uterus grows a new, thickened lining (endometrium) that can hold a fertilized egg. When there is no fertilized egg to start a pregnancy, the uterus then sheds its lining. The menstrual cycle has three distinct phases: the follicular phase (FP), ovulation and the luteal phase (LP). The FP begins on day one of menstruation and lasts about 10-14 days, until ovulation (the monthly release of a mature egg from an ovary). The LP or secretory phase is the second half of the menstrual cycle after ovulation. Estrogen and progesterone concentrations vary between the phases.
3) Does lactate accumulation during exercise inhibit fat breakdown?
No, lactate accumulation from higher intensity exercise does not inhibit lipolysis (Jeukendrup, 2002).
4) What is the female athlete triad?
The female athlete triad is a condition that consists of lack of a menstrual cycle, low bone mineral density and eating disorders. This occurs in females whose training levels exceed energy availability. Some of the health consequences include cardiovascular, endocrine, reproductive, skeletal, gastrointestinal, renal and central nervous system complications. Psychological problems associated include low self-esteem, depression and anxiety disorders. The first goal of treatment for the female athlete triad sufferer is to increase energy availability by increasing intake of foodstuffs and/or reducing energy expenditure. Females with eating disorders or disordered eating patters should be referred for nutritional counseling. Source: Nattiv et al., 2007
5. What is menopause?
Menopause represents a normal, but major transition period in a woman's health, which marks the time menstruation ceases. A fundamental etiology associated with menopause is the intricate link between estrogen metabolism and the autonomic nervous system. Irregular or menstrual periods changes are usually the first symptom. Lower fertility during the peri-menopausal (transition into menopause that begins 8 to 10 years before menopause) stage of a woman's life results in significant drops in estrogen levels. The term vaginal atrophy refers to an inflammation of the vagina as a result of the thinning and shrinking of the tissues, as well as decreased lubrication caused by a lack of estrogen. Hot flashes, a sudden feeling of heat in the upper body may start in the face, neck or chest, and then spread upwards or downwards (depending on where it started). The skin on the face, neck or chest may redden, and a woman usually starts to sweat. The heart rate may suddenly increase and may become irregular or stronger than usual. Hot flashes generally occur during the first year after a woman's final period. Disturbed sleep problems are generally caused by night sweats, insomnia or anxiety. Difficulty falling asleep and staying asleep increase as women go through menopause. Urinary problems tend to be more susceptible during this period. Moodiness often goes hand-in-hand with sleep disturbance. There also may also be some hair loss or thinning during menopause.
Source: Nordqvist, C. (2009). Medical News Today.
6. Is walking as effective as vigorous exercise for the prevention of cardiovascular events in women.
Manson et al. compared walking and vigorous exercise, and hours spent sitting as predictors of the incidence of coronary events and total cardiovascular events among 73,743 postmenopausal women 50 to 79 years of age in the Women's Health Initiative Observational Study. The data indicate that both walking and vigorous exercise are associated with substantial reductions in the incidence of cardiovascular events among postmenopausal women, irrespective of race or ethnic group, age, and body-mass index. Prolonged sitting predicts increased cardiovascular risk.
7. Are women at an increased risk for cardiovascular disease after menopause?
Yes. Women who are pre- and postmenopausal are at an increased risk for injury, due to a decrease in the female sex hormones.
8. Does estrogen affect skeletal muscle damage, inflammation and repair?
Yes, estrogen may positively lesson skeletal muscle damage and inflammation from exercise. As well, theoretical evidence suggests estrogen may encourage recovery and repair of muscle as well. This research is preliminary and more research is needed to explore mechanisms and further applications (Tiidus, 2003).
9. Does hormone replacement affect exercise performance?
Green et al (2002) found that hormone replacement during exercise in postmenopausal women was only observed during high intensity aerobic exercise. Systolic blood pressure at peak exercise in women taking hormones was found to be less than in women not taking hormones at almost identical levels of oxygen consumption and cardiac output. Further research is needed in this area.
10. Is weight gain during menopause inevitable or preventable?
The years during menopause are associated with weight gain and increased central adiposity. Body fat distribution and body composition changes may be due to the hormonal changes occurring during the menopausal transition and loss of muscle mass. Importantly, the one factor most consistently related to weight gain during menopause, however is physical inactivity. To avoid this weight gain, women should make regular physical activity a priority (Simkin-Silverman et al., 2003).

References:
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http://www.medicalnewstoday.com/articles/155651.php
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Bios:
Len Kravitz, PhD, is the program coordinator of exercise science and a researcher at the University of New Mexico, Albuquerque, where he won the Outstanding Teacher of the Year award. He has received the prestigious Can-Fit-Pro Lifetime Achievement Award and American Council on Exercise Fitness Educator of the Year.
Afton Cazares, MA, is a doctoral student in Exercise Science at the University of New Mexico, Albuquerque. She holds a masters in Human Performance and Sport, with a concentration in Exercise Science from New Mexico Highlands University, Las Vegas, New Mexico. Her research interests are in women's health, exercise testing and training and tactical strength and conditioning.
Christine Mermier, Ph.D. is an assistant professor and Exercise Physiology laboratory director in the Exercise Science Program at UNM. Her research interests include the effect of exercise in clinical patients, women, and aging populations, and high altitude physiology.
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