Sex Hormones, Exercise and Women Scientific and Clinical

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This work is dedicated to my good friend
and mentor, the late Dr. Atko Viru, of Tartu
University, Estonia.
Preface

In the late 1970s medical science was beginning to understand that exercise train-
ing, while normally an extremely positive physiological stimulus, could also have
some drawbacks. Landmark research studies by scientists such as Dr. Barbara
Drinkwater, Dr. Anne Loucks, and Dr. Michelle Warren, as well as others, demon-
strated that exercise training could be a causative factor in disrupting the endocrine
control of a woman’s reproductive system leading to the development of “athletic
amenorrhea” (secondary amenorrhea). This medical condition is now recognized as
part of the conditions associated with the Female Athletic Triad.
The basic premise of the research work on the development of athletic amenor-
rhea in women can be conceptualized as follows:
Exercise → Female Reproductive Hormones → Physiologic Consequences (negative)
That is, aspects of exercise and exercise training modulate the functioning of the
female reproductive hormones. This modulating influence can be highly negative,
leading to low estrogen and progesterone states and disruption of normal ovary
function and menstruation. Contemporary research has demonstrated that the criti-
cal aspects initiating the sequence of such events are energy availability (i.e., devel-
opment of a low energy availability state; recently designated as part of the Reduced
Energy Deficient in Sports conditions [REDS] by an International Olympic
Committee medical commission).
As a young professional I found the research on athletic amenorrhea an exciting
and fascinating aspect of exercise endocrinology. But my curiosity also caused me
to think about the relationship in a different fashion and ask the question—If exer-
cise affects reproductive hormones, could the reproductive hormones have physio-
logical effects unrelated to reproduction that influences the capacity of women to
exercise? This seemed a logical question to me as many hormones have more than

vii
viii Preface

one physiological effect/impact, and structurally many reproductive hormones have

chemical structures similar to many metabolic and water balance hormones. In
other words I wondered:
Female Reproductive Hormones → Exercise → Physiologic Consequences
(negative/positive?)
After studying the research literature, it was apparent that animal researchers had
been asking this question and seeing that the female reproductive hormones did
affect physiological systems and processes that affected exercise capacity. At that
time, nearly 30 years ago, the human-based literature was extremely sparse. With
that, I and a number of other researchers began to pursue the question of whether the
female reproductive hormones have physiological impacts on the bodily systems
that are essential to the exercise capacity of women exercisers.
In asking this question, to myself, the underlying premise was not to examine
women to see why in some activities men are better. But, more to understanding the
unique physiology of women and whether female sex hormones might account for
some of the variance in physiological performance between amenorrheic and
eumenorrheic women, and within women across the age span as they experience
menarche to menopause. That has been my interest in pursuing this absorbing topic
and why I wanted to develop this book.
This book was developed with hope that the select group of professionals writing
the various chapters could address this last question. Like nearly all written works,
this one could be improved and be made better, but I am extremely proud and thank-
ful to the authors who contributed and put forth so much hard work. Each discussed
topic provides current insight into the state-of-the-art research in the respective
topic area. It is hoped the reader will be as excited and fascinated after reading the
individual topics as the authors were in writing them. I also hope the insights pro-
vided here will inspire new researchers to ask questions about the roles of female
sex hormones in exercise and pursue investigations to seek answers to those
questions.

Chapel Hill, NC, USA Anthony C. Hackney, PhD, DSc

Acknowledgments

I wish to acknowledge the support of my graduate students who certainly helped me

bring this to completion. You are a great group of young professionals.

Thanks

My sincere thanks to all the authors involved with this project. They were wonderful
to work with and I appreciate their professionalism. I also wish to sincerely thank
my family for their support while I worked on this project.

ix
Contents

1 The Hypothalamic–Pituitary–Ovarian Axis

and Oral Contraceptives: Regulation and Function............................ 1
Hope C. Davis and Anthony C. Hackney
2 Sex Hormones and Their Impact on the Ventilatory
Responses to Exercise and the Environment ........................................ 19
Joseph W. Duke
3 Sex Hormones and Substrate Metabolism
During Endurance Exercise ................................................................... 35
Laurie Isacco and Nathalie Boisseau
4 Sex Hormone Effects on the Nervous System and their Impact
on Muscle Strength and Motor Performance in Women .................... 59
Matthew S. Tenan
5 Estrogen and Menopause: Muscle Damage, Repair
and Function in Females ........................................................................ 71
Peter M. Tiidus
6 Nutritional Strategies and Sex Hormone Interactions in Women ...... 87
Nancy J. Rehrer, Rebecca T. McLay-Cooke and Stacy T. Sims
7 The Effect of Sex Hormones on Ligament Structure,
Joint Stability and ACL Injury Risk ..................................................... 113
Sandra J. Shultz
8 Sex Hormones and Physical Activity in Women:
An Evolutionary Framework ................................................................. 139
Ann E. Caldwell and Paul L. Hooper
9 Sex Hormones and Environmental Factors Affecting Exercise .......... 151
Megan M. Wenner and Nina S. Stachenfeld

xi
xii Contents

10 Exercise, Depression-Anxiety Disorders and Sex Hormones .............. 171

Shannon K. Crowley
11 Stress Reactivity and Exercise in Women ............................................. 193
Tinna Traustadóttir
12 Sex Hormones, Cancer and Exercise Training in Women .................. 209
Kristin L. Campbell
13 The Effects of Acute Exercise on Physiological Sexual Arousal
in Women ................................................................................................. 227
Cindy M. Meston and Amelia M. Stanton
14 Sex Hormones, Menstrual Cycle and Resistance Exercise.................. 243
Yuki Nakamura and Katsuji Aizawa
15 Effects of Sex Hormones and Exercise on Adipose Tissue .................. 257
Victoria J. Vieira-Potter
16 Exercise in Menopausal Women ............................................................ 285
Monica D. Prakash, Lily Stojanovska, Kulmira Nurgali
and Vasso Apostolopoulos

Index ................................................................................................................. 309

Contributors

Katsuji Aizawa, Ph.D. Senshu University, Kanagawa, Japan

Vasso Apostolopoulos, Ph.D. Centre for Chronic Disease, College of Health and
Biomedicine, Victoria University, Melbourne, VIC, Australia
Nathalie Boisseau, Ph.D. Laboratory of the Metabolic Adaptations to Exercise
under Physiological and Pathological Condition, Clermont Auvergne University,
Clermont-Ferrand, France
Ann E. Caldwell, Ph.D. Anschutz Health and Wellness Center, University of
Colorado Denver, School of Medicine, Aurora, CO, USA
Kristin L. Campbell, P.T., M.Sc., Ph.D. Department of Physical Therapy, Faculty
of Medicine, University of British Columbia, Vancouver, BC, Canada
Centre of Excellence in Cancer Prevention, School of Population and Public Health,
Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
Shannon K. Crowley, Ph.D. Department of Exercise Science, North Carolina
Wesleyan College, Rocky Mount, NC, USA
Hope C. Davis, M.A. Human Movement Science Curriculum, University of North
Carolina, Chapel Hill, NC, USA
Joseph W. Duke, Ph.D. Department of Biological Sciences, Northern Arizona
University, Flagstaff, AZ, USA
Anthony C. Hackney, Ph.D., D.Sc. Department of Nutrition, University of North
Carolina, Chapel Hill, NC, USA
Department of Exercise & Sport Science, University of North Carolina, Chapel
Hill, NC, USA
Paul L. Hooper, Ph.D. Department of Anthropology, Emory University, Atlanta,
GA, USA

xiii
xiv Contributors

Laurie Isacco, Ph.D. Laboratory of Prognostic Markers and Regulatory Factors of

Cardiovascular Diseases and Exercise Performance Health Innovation Platform,
University of Bourgogne Franche-Comte, Besançon, France
Rebecca T. McLay-Cooke, B.Ph.Ed., B.Sc., M.Sc. Department of Human
Nutrition, University of Otago, Dunedin, Otago, New Zealand
Cindy M. Meston, Ph.D. Department of Psychology, The University of Texas at
Austin, Austin, TX, USA
Yuki Nakamura, Ph.D. St. Margaret's Junior College, Tokyo, Japan
Kulmira Nurgali, M.B.B.S., Ph.D. College of Health & Biomedicine, Victoria
University, Melbourne, VIC, Australia
Monica D. Prakash, Ph.D. Centre for Chronic Disease, College of Health and
Biomedicine, Victoria University, Melbourne, VIC, Australia
Nancy J. Rehrer, B.A., M.Sc., Ph.D. School of Physical Education Sport &
Exercise Sciences, University of Otago, Dunedin, Otago, New Zealand
Sandra J. Shultz, Ph.D., A.T.C. Department of Kinesiology, University of North
Carolina at Greensboro, Greensboro, NC, USA
Stacy T. Sims, B.A., M.Sc., Ph.D. Health, Sport and Human Performance,
University of Waikato, Adams Centre for High Performance, Mount Maunganui,
New Zealand
Nina S. Stachenfeld, Ph.D. Department of Obstetrics, Gynecology and
Reproductive Sciences, The John B. Pierce Laboratory and Yale School of Medicine,
New Haven, CT, USA
Amelia M. Stanton, B.A. Department of Psychology, The University of Texas at
Austin, Austin, TX, USA
Lily Stojanovska, M.Sc., Ph.D. Centre for Chronic Disease, College of Health
and Biomedicine, Victoria University, Melbourne, VIC, Australia
Matthew S. Tenan, Ph.D. United States Army Research Laboratory, Aberdeen
Proving Ground, Adelphi, MD, USA
Peter M. Tiidus, B.Sc., M.Sc., Ph.D. Faculty of Applied Health Sciences, Brock
University, St. Catharines, ON, Canada
Tinna Traustadóttir, Ph.D. Department of Biological Sciences, Northern Arizona
University, Flagstaff, AZ, USA
Victoria J. Vieira-Potter, Ph.D. Department of Nutrition and Exercise Physiology,
University of Missouri, Columbia, MO, USA
Megan M. Wenner, Ph.D. Department of Kinesiology and Applied Physiology,
University of Delaware, Newark, DE, USA
Chapter 1
The Hypothalamic–Pituitary–Ovarian Axis
and Oral Contraceptives: Regulation
and Function

Hope C. Davis and Anthony C. Hackney

Introduction

Over the past few generations female participation in sports has continued to
increase, which has resulted in a greater need for research in the area of sports
medicine, physiological effects, and consequences of exercise by women. Specific
further work is still needed particularly in the area of reproductive endocrinology.
The female reproductive system is a complex physiological system consisting of
many hormonal and regulatory components. Thus, it is imperative for exercise sci-
entists who wish to study the female reproductive system to have a strong knowl-
edge base of the controlling regulatory axis of the system, referred to as the
Hypothalamic–Pituitary–Ovarian (HPO) axis.
The intent of this chapter is to provide such background information about the
neuroendocrine basics of the female reproductive system relative to: the hypo-
thalamus, the pituitary, the ovary, and the uterus. The chapter focuses on provid-
ing a brief review of the essential endocrinology of the menstrual cycle in health
females as well as providing information about oral contraceptive (OC) function
and use. This context provides an essential framework for discussions provided
in subsequent chapters in this book.

H.C. Davis, M.A.

Human Movement Science Curriculum, University of North Carolina, Chapel Hill, NC, USA
A.C. Hackney, Ph.D., D.Sc. (*)
Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
Department of Exercise & Sport Science, University of North Carolina,
Chapel Hill, NC, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2017 1

A.C. Hackney (ed.), Sex Hormones, Exercise and Women,
DOI 10.1007/978-3-319-44558-8_1
2 H.C. Davis and A.C. Hackney

Hypothalamic–Pituitary System

Proper functioning of the reproductive system is critical not only to reproductive health,
but overall health in women. Abnormal reproductive health can sometimes be character-
ized by amenorrhea and, or other medical maladies (see later discussion, this chapter).
Regulation of the female reproductive system consists of complex interactions
between endocrine feedback loops of the hypothalamus, pituitary, and ovary.
Although there is debate whether the hypothalamus or pituitary is the most impor-
tant regulator in the process, there is no denying that all three neuroendocrine glands
must work together to ensure proper functioning (Sam and Frohman 2008).
The signaling process begins in the hypothalamus, where gonadotropin-­releasing
hormone (GnRH) is released into the blood stream and travels to the pituitary gland.
The pituitary responds by releasing gonadotropin hormones, specifically luteinizing
hormone (LH) and follicle stimulating hormone (FSH) in females. The anterior
pituitary also releases growth hormone (GH), thyroid-stimulating hormone (TSH),
prolactin, and adrenal corticotrophin hormone in response to a variety of other
hypothalamic stimuli; these other hormones control primarily growth-development,
metabolism, and responses to stress. The posterior pituitary produces hormones as
well, namely oxytocin and antidiuretic hormone (ADH; also called vasopressin).
Oxytocin controls lactation as opposed to growth and development, and ADH func-
tions with aldosterone (released by adrenal cortex) to maintain fluid and electrolyte
balance (Brooks et al. 2005). In healthy women GnRH is released in a pulsatile
manner, and consequently FSH and LH are released in a similar pulsatile pattern
from the anterior pituitary (Speroff and Fritz 2005).
Current research suggests that a set of brain peptides encoded by the Kiss1 gene,
known more commonly as kisspeptin, may be an important upstream regulator in
GnRH release in humans as well as many other mammalian species (Lapatto et al.
2007). Kisspeptin neurons in the hypothalamus modulate the prepubescent LH surge
that occurs in females as well as the actions of sex steroids on GnRH neurons (Gu and
Simerly 1997). This regulation of the reproductive axis is illustrated by the reproduc-
tive defects that exist in mice and other mammals when the kisspeptin receptor gene
is disrupted (Dungan et al. 2007). Additional physiological parameters, such as meta-
bolic disruptions (e.g., under nutrition), can decrease kisspeptin expression, which in
turn can suppress reproductive functioning (Castellano et al. 2005; Luque et al. 2007).

Sex Steroid Hormones

Estrogen

Estrogen is one of the two major reproductive hormones released as a result of

the HPO axis activity. Estrogen refers to a group of similarly structured steroid
hormones that are produced primarily in the ovaries of females. The estrogen
group is made up of estrone, estriol, and estradiol-β-17, the latter of which
1 The Hypothalamic–Pituitary–Ovarian Axis and Oral Contraceptives… 3

contributes primarily to reproductive function (Wierman 2007). These estrogens

have physiological roles in both males and females, including soft tissue, skel-
etal muscle, and the epidermis (Wierman 2007). The estrogens (estrone and
estriol) are essentially produced locally in target tissue (peripheral conversion)
such as adipose cells. Estradiol-β-17, the estrogen primarily produced at the
ovaries, is responsible for primary and secondary female sex characteristics and
therefore is the main estrogen discussed in this chapter.
As previously stated, the HPO axis is the main regulator of estrogen production
in women. The pituitary release of FSH and LH results in binding to the ovarian
receptors for these hormones, which induces the production and secretion of both
estrogen and progesterone (see later section; Ferin 1996).
Specifically within the ovary, LH binds to LH receptor cites on the thecal cells.
When stimulated, they convert available cholesterol into androgens (McNatty et al.
1979). These androgens are then transported to the granulosa cells where FSH binds
to FSH receptors, thus stimulating conversion of androgens into estradiol-β-17 via
aromatase enzymes (Hillier 1987).
Estrogen gradually increases during the follicular phase of the menstrual cycle in
order to support the developing oocyte (McNatty et al. 1979). Once the egg is
released from the ovary, the follicle shifts from estrogen to progesterone production
and estrogen levels slowly decrease throughout the luteal phase of the cycle.
Although the ovary will still produce estradiol-β-17 during the cycle, it will be in
conjunction with progesterone, thus decreasing the overall concentration and effec-
tiveness of estrogen (see discussion later section).
Recent studies have found that natural mutation of estrogen receptors (ERs) or
deficiency of aromatase (the enzyme that converts androgens to estradiol-β-17 in the
ovary and some peripheral tissues) results in tissue specific deficits, including the
vascular system, central nervous system, gastrointestinal tract, immune system, skin,
kidney, and lungs (Couse and Korach 1999; Curtis and Korach 2000; Eddy et al.
1996; Hewitt and Korach 2003; Matsumoto et al. 2005; Robertson et al. 1999).
Lastly, physiological estradiol-β-17 can increase lipolysis and inhibit glycogen utili-
zation during rest and acute exercise (Hackney 1999). It is thought that estradiol-β-17
may directly alter enzymatic activity or indirectly affect insulin sensitivity thereby
affecting glycogen usage (Bunt 1990). Estrogens not only control primary and sec-
ondary sex characteristics in females, but also regulate a number of functions
throughout female and male target tissues in the body through its direct and indirect
impacts on other neuroendocrine agents (Bunt 1990; see Fig. 1.1 and 1.2).

Progesterone

Progesterone is the second major reproductive hormone produced and regulated

via the HPO axis. Progesterone is the major progestogen (steroid hormone clas-
sification) and is produced predominately by the ovaries, but it is also produced
locally in some tissues. Similarly to estradiol-β-17, LH regulates progesterone
production within the ovary. During the luteal phase of the menstrual cycle, LH
 Relative Hormonal Changes

LH

Progesterone

FSH Estrogen

Day Day Day

1 14 28
Menstruation Ovulation Menstruation
Follicular Phase Luteal Phase

Fig. 1.1 Figure displays the typical key regulatory hormone changes associated with the men-
strual cycle in a healthy eumenorrheic woman

METABOLIC ACTIONS Anterior

OF ESTROGEN Pituitary
E2
E2
E2

Pancreas
Adrenal
GH Gland
E2 In/G Ratio
Gluconeogenesis
Glycogenolysis
Cortisol
FA Synthase

Liver Lipolysis

TG E2
E2

In Sensitivity
HS-Lipase
Skeletal Muscle Adipose
Tissue

E2 FFA
Estrogen Direct Indirect

Fig. 1.2 Figure illustrates of the direct (solid line arrows) and indirect (dashed line arrows) effects
of estrogen (E2) on a variety of hormones and physiologic processes associated with many critical
aspects of regulating energy metabolism and energy substrate availability. Abbreviations: FFA free
fatty acids, G glucagon, GH growth hormone, In insulin, TG triglycerides. Symbols: ↑ = increase;
↓ = decrease; Δ = delta (change)
1 The Hypothalamic–Pituitary–Ovarian Axis and Oral Contraceptives… 5

stimulates LH receptors on luteinized granulosa cells of the ovary, leading to the

conversion of cholesterol to both progesterone and estrogen (Filicori 1999).
Progesterone stabilizes the endometrial lining in preparation for fertilization and
pregnancy (Filicori 1999). When progesterone concentrations are high, progester-
one can inhibit binding of estrogen to an ER by blocking the binding site . This
causes the conversion of estradiol-β-17 to estrone, a less active form of estrogen
(Erickson et al. 1985). Progesterone also has important effects on the central ner-
vous system, vascular tissue, and other target tissues (Mani et al. 1997; please see
other chapters in book for details).

The Ovary

As previously stated, the ovary is responsible for the production of estrogen and
progesterone, but it is also responsible for the maturation and release of the
oocytes, or eggs, during the luteal phase of the menstrual cycle. The ovary is made
of the outer cortex, the inner medulla, and the hilum, but it is the outer cortex that
is considered the functional component of the ovary. This outer portion contains
the follicles that produce and release mature eggs as well as estrogen and proges-
terone (Speroff and Fritz 2005).

Oocytes

The oocytes in the outer cortex begin to develop around the seventh week of fetal
life. Oogonias, or germ cells, form along the gonadal ridge of the fetus surrounded
by a developing follicle. This follicle is made of a fluid-filled cavity surrounded by
granulosa and thecal cells. These oogonias undergo rapid mitosis and can reach up
to six to seven million in the ovary. The oogonias will become oocytes and diminish
in number via follicular atresia throughout a female’s lifetime (Himelstein-Braw
et al. 1976; Motta et al. 1997). When the oocytes in the ovary have been depleted, a
woman will undergo menopause (typically the fourth to fifth decade of life) and
stop releasing eggs from the ovaries. Interestingly, the majority of these oocytes will
be depleted before females reach puberty. Just 300,000–500,000 oocytes exist at the
start of puberty, and only 400–500 will actually go through ovulation, with the rest
starting the process but undergoing programmed apoptosis prior to release from the
follicle (Himelstein-Braw et al. 1976; Motta et al. 1997).

Ovulation and Ovarian Hormone Production

At the onset of puberty, the hypothalamus begins to release GnRH in a pulsatile

fashion, thus releasing the gonadotropins, FSH and LH (see earlier overview in this
chapter). As noted, these hormones result in the release of the sex steroid hormones
6 H.C. Davis and A.C. Hackney

progesterone and estrogen at the ovary as well as the designation of which follicle
will complete ovulation.
Within each follicle, thecal cells have LH receptors which when stimulated con-
vert cholesterol to androgen. The androgen then moves to the layer of granulosa
cells where it serves as a substrate and produces estrogen via intracellular aromatase
enzymes stimulated by FSH (Hillier 1987).
Each month, between 3 and 11 follicles begin to grow independently of hormone
influence (Gougeon 1986). Increasing levels of FSH induces granulosa cells to
increase the number of FSH receptors on their cell membranes (Mais et al. 1986). This
feed forward regulatory system exponentially increases sensitivity of FSH in the gran-
ulosa cells, and the cell with the most receptors and therefore the highest sensitivity to
FSH will become the dominant follicle during the menstrual cycle. The dominant fol-
licle then secretes an increased amount of estrogen in response to the increased andro-
gen substrate supply in order to support the oocyte (McNatty et al. 1979).
Luteinization, the process of progesterone production to prepare the endometrial
lining for development of an embryo, is dependent on LH. In turn, LH stimulates
LH receptors on the granulosa cells, which leads to the conversion of cholesterol to
progesterone and estrogen (Filicori 1999). Circulating progesterone levels can also
block FSH and LH receptors in order to prevent new follicle growth during this time
(Nippoldt et al. 1989).
Additionally, there are several less widely known reproductive sex hormones
that should be mentioned. Granulosa cells produce inhibin, which inhibits FSH
secretion in remaining follicles that have not been selected as the dominant follicle,
and activin, which stimulates FSH and increases the sensitivity of FSH at the ovary
(Kitaoka et al. 1988). Follistatin is an additional hormone that inhibits activin and is
released by the anterior pituitary (Besecke et al. 1997).

The Menstrual Cycle

The fluctuating production and release of these reproductive hormones over approxi-
mately 28 days is known as the menstrual cycle. It consists primarily of low-­estrogen
(follicular) and high-estrogen (luteal) phases, which are divided by the ovulatory
period (~mid-cycle). Day One begins on the first day of menses (bloody discharge),
or the first day of withdrawal bleeding, and is the start of the follicular phase. During
this time the dominant follicle is selected (see earlier discussion). This stage is char-
acterized by increasing FSH and low-estrogen due to regression of the corpus luteum
from the previous cycle. With increased sensitivity of FSH due to FSH receptors on
the granulosa cells, a dominant follicle is selected and begins to secrete estrogen.
Mid-cycle, a positive feedback loop emerges as increasing estrogen levels from the
follicle stimulate the LH surge characteristic of the luteal phase (Pauerstein et al.
1978). Following ovulation, progesterone is released in a pulsatile manner from the
follicle in response to the LH surge. The follicle then becomes the corpus luteum
within the uterus (Vande Wiele et al. 1970). If fertilization occurs, the embryo remains
1 The Hypothalamic–Pituitary–Ovarian Axis and Oral Contraceptives… 7

in the endometrium and develops into a fetus. If no fertilization occurs the corpus
luteum is degraded via proteolytic enzymes (Brannian and Stouffer 1991). This is
accompanied by a fall in estrogen and progesterone and the onset of menstruation.
The entire cycle takes approximately 28 days, although the cycle ranges from 21 to
35 days (Nelson 2014) in a healthy adult female. Then the cycle begins again with the
start of menstruation and the follicular phase. Figure 1.1 gives an illustrative display
of the major circulating hormonal changes over the menstrual cycle.

The Uterus

During the menstrual cycle, an oocyte travels from the ovary to the uterus, where it
is either fertilized or shed along with the menstrual tissue. This section provides a
basic overview of the anatomy and function of the uterus and its key role within the
menstrual cycle.

Anatomy

The anatomy of the uterus consists of the fundus, the corpus, the cornu, and the
cervix. The uppermost region of the uterus consists of the fundus, and it is the usual
site of embryo development if fertilization occurs. The corpus is the body, and the
cornu is the site of the insertion of the fallopian tubes. The cervix is the bottom most
portion and connects the uterus to the vagina (Smout et al. 1969). The uterus has
three layers: the mesometrium, which is the innermost layer, the myometrium, and
the endometrium, which is the outermost layer. Each layer consists of multiple
smooth muscles (Smout et al. 1969).

Uterine Phases

The uterus goes through two phases during a menstrual cycle as well: the prolifera-
tive phase corresponds with the follicular phase while the secretory phase aligns
with the luteal phase of the ovary. In the proliferative phase, circulating estrogen
contributes to endometrial gland growth as well as stroma and endothelial cell
number growth (Ludwig and Spornitz 1991). Post ovulation, progesterone levels
increase corresponding to the secretory phase of the uterus. Circulating progester-
one blocks the binding site on estrogen receptors, thus suppressing endometrial
growth. Progesterone also causes the conversion of estradiol-β-17 to estrone
(Falany and Falany 1996). Nearing the end of the cycle, the corpus luteum disap-
pears. The stroma and glands undergo apoptosis, and the endometrium shrinks
causing the spiral arteries to oscillate between vasospasm and vasodilation. This
change can cause tissue ischemia and inflammation and leads to an increase