The Active Female: Health Issues Throughout the Lifespan 2008th Edition

7. Effects of the Menstrual Cycle on the Acquisition of Peak Bone Mass

Mimi Zumwalt  and Brittany Dowling 

(1)

Department of Orthopaedic Surgery and Rehabilitation, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430-9436, USA

(2)

Department of Health, Exercise, and Sports Sciences, Texas Tech University, 1545 Shadowtree Court, Colorado Springs, CO 80921, USA

Mimi Zumwalt (Corresponding author)

Email: mimi.zumwalt@ttuhsc.edu

Brittany Dowling

Email: dowlingb86@gmail.com

Abstract

The menstrual cycle has huge implications on the building, maintenance, and break down of skeletal bone in women. Due to the fluctuating level of female hormones, the menstrual cycle plays a different role during various times of the month which in turn affects bone health. Estrogen is a crucial hormone for bone turnover/remodeling which, when released, provides a protective mechanism against the process of natural bone loss due to aging. Acquiring a high amount of peak bone mass during adolescence helps to protect the female athlete against rapid degradation of bone due to the decline of estrogen around menopause. Therefore, taking appropriate steps years before and after menopause is crucial in order to preserve bone mass in females.

Keywords

Menstrual cycleEstrogenBone turnover/remodelingPeak bone mass

7.1 Learning Objectives

At the completion of this chapter, you should have an understanding of the following:

Table 7.1

Classification of bone mineral density according to the World Health Organization

Normal bone density

<1

Standard deviation (SD) below the mean

Osteopenia

1–2.5

SD below the mean

Osteoporosis

>2.5

SD below the mean

Severe osteoporosis

>2.5

SD below the mean/fragility fracture(s)

·               The pertinent female reproductive anatomy and physiology of a normal menstrual cycle, including the different phases and roles of various hormones

·               The different components of bone along with its function, biochemistry, and metabolism

·               The interaction between different ovarian hormones and various bone components

·               The definition, importance, and effective methods of achieving peak bone mass

·               The results of an abnormal menstrual cycle on attainment of peak bone mass, how to go about assessing/measuring bone density, and ways to address this issue further to help minimize bone loss and maintain bone density

7.2 Introduction

Bone tissue has various functions; however, its primary function is to provide structural and mechanical support for soft tissues. Because the skeleton provides structural support for body, having the maximal amount of strong bones will serve to protect against osteoporosis (decreased bone mass due to bone loss) later on in life [1]. Bone is far from static; in fact, this living tissue is quite dynamic. New bone continually remodels and repairs old bone depending on mechanical, physiological, and hormonal stimuli. The latter, systemic hormonal milieu, plays a very important role during puberty and in females is manifested by the menstrual cycle [24]. There is no evidence for gender difference in bone mineral density (BMD) at birth, and accrual rates stay the same until puberty, where sex differences become pronounced. Studies have found 40–50 % of adult peak bone mass is accumulated during puberty [5] and peak bone mass is achieved around ages 25–35 years [6]. During the teenage years 60–90 % of all skeletal bone is laid down [810]. Genetics predetermine 60–80 % of skeletal development; however, environmental factors (diet, energy availability, physical stress) account for 20–40 % of developing bone [348]. The amount of bone mass that is gained during this adolescent period equates to the quantity of bone that will be lost during the rest of one’s adult life [1011]. Therefore, measures to maximize and protect the quantity of bone developed during the growing period is advantageous and will serve the body well in activities of daily living and other life endeavors beyond these early years [12].

This chapter will focus primarily on the female menstrual cycle and its influence on peak bone mass achieved during and after adolescence.

7.3 Research Findings and Contemporary Understanding of the Issues

7.3.1 Anatomy of the Female Sex Organs and Physiology of the Menstrual Cycle

The female reproductive system is a multiorgan system comprised of the hypothalamus, pituitary gland, ovaries, uterus, and vagina (Fig. 7.1).

A145875_2_En_7_Fig1_HTML.gif

Fig. 7.1

Female reproductive unit

Pertinent anatomy involved with the menstrual cycle includes the ovaries, a paired organ which has both a reproductive and an endocrine function. This is where eggs are formed and female sex hormones are produced [1314]. Three levels of hormones are normally secreted in a feedback loop termed the hypothalamic-pituitary-ovarian (HPO) axis [15]: (1) by the hypothalamus—gonadotropin-releasing hormone (GnRH); (2) by the anterior pituitary—follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in response to GnRH; and (3) by the ovaries—two gonadal steroids, estrogen and progesterone, in response to FSH and LH. Regulation of the menstrual cycle is controlled by both LH and FSH from the anterior pituitary gland in response to GnRH from the hypothalamus [16]. As discussed in prior chapters, these hormones are secreted in different amounts during various phases of the monthly menstrual cycle [314]. The onset of menarche in females signals the transition from childhood to the pubertal, reproductive state, correlating with both body height and bone maturation [15]. Menarche normally occurs about two years after the appearance of secondary sex characteristics (breast and pubic hair development) around age 11–13 years, but can begin as early as 7 years old [914]. Menarche is relatively a late determinant of pubertal development [17]. If menstruation does not occur by age 16, this delay of menarche (primary amenorrhea) may be due to excessive exercise or insufficient intake of appropriate nutrition, among other factors [1617].

The menstrual cycle occurs on a regular basis between 20 and 45 days, on average approximately every 4 weeks (28 days), with menstrual flow lasting from 3 to 7 days [7914]. Typically, three separate phases encompass the normal menstrual cycle: (1) follicular or proliferative phase (growth of the endometrium or uterine lining stimulated by estrogen), (2) ovulatory phase (ovulation or egg release in response to LH), and (3) luteal or secretory phase (transformation of the endometrium from a proliferating into secreting-type tissue under progesterone influence) [1618]. The duration of the follicular phase is more variable between different women, whereas the luteal phase is consistently 14 days [7]. The first day of the menstrual cycle is marked with the initial sign of vaginal bleeding. The onset of the follicular phase is stimulated by FSH more so than LH; the quantity of LH slowly increases during the follicular phase until peaking levels at mid-cycle. High amounts of FSH during the beginning of the luteal phase stimulate growth of several ovarian follicles then levels begin to decline until late luteal phase [7]. During this time both progesterone and estrogen serum levels are low. Estrogen then increases steadily, peaking just before ovulation, generally occurring on the same day of the LH surge [7]. This rise in estrogen occurs about the middle of the cycle, day 14, when one follicle is released in the ovulation phase. The luteal phase then takes over during the second half of the cycle under the continuing influence of LH. Progesterone then increases above estrogen levels, though the latter hormone concentration remains fairly high. These two hormones, estrogen and progesterone, are secreted by the corpus luteum which then degenerates, causing both hormonal levels to concurrently fall as long as the egg is neither fertilized nor implanted in the uterus. The monthly cycle then repeats itself by shedding of the endometrium, manifested by menstrual flow, to restart the follicular phase all over again under FSH influence [914] (Fig. 7.2).

A145875_2_En_7_Fig2_HTML.gif

Fig. 7.2

Menstrual cycle. FSH, follicle stimulating hormone; LH, lutenizing hormone

7.3.2 Effects of Female Sex Hormones on Bone

The female reproductive system plays a major role in the maintenance of the skeletal bone integrity from menarche to menopause. The skeleton is one of the main target tissues for estrogen, and to a lesser extent, progesterone. Bone cells contain estrogen and progesterone receptors that positively stimulate bone formation and suppress bone resorption. Thus, they are key regulators of bone turnover, adjusting the bone mass “set point” by keeping in balance the quantity of bone being formed with the amount that is reabsorbed (coupling effect) [1015]. Sex hormone receptors have been found in growth plate chondrocytes (cartilage cells) during puberty [17]. At the early stages of puberty, sex hormones stimulate longitudinal bone lengthening of the diaphyses (shafts of long bones) resulting in the “pubertal growth spurt” [6]. Estrogen acts indirectly through inhibiting bone resorption by osteoclasts while increasing the activity of bone forming cells, osteoblasts (discussed further below in Sect. 7.3.3) [414]. However, at the late stages of puberty the sex-specific hormones, primarily estrogen, play a large role in the closure of growth plates. Estrogen, therefore, highly influences the final height achieved in females [14].

Estrogen and progesterone not only play an essential role on homeostasis of the skeleton by exerting their direct effects through receptors on bone cells but also exert indirect effects on other systemic hormones. These sex hormones work in conjunction with other hormones and steroids to further facilitate bone development. For example, estrogen regulates circulating levels of growth hormone (GH) and insulin growth-like factor (IGF-1); these two hormones stimulate longitudinal bone growth [117]. In a cross-sectional study conducted on children, serum IGF-1 levels were positively associated with bone growth [6]. Insulin growth-like factor receptors (IGF-1R) are also located in the kidneys, where they are associated with the production of the hormonal form of vitamin D [17]. Environmental factors can also stimulate bone formation. Mechanical loading of bone exerts a positive effect on bone formation at points of stress, in a process defined by Wolff’s Law. A cross-sectional study found hip and spine BMD values 30–40 % greater in female gymnasts compared to long-distance runners. This implies that the higher impact forces generated in gymnastics (10–12 times body weight) as compared to running (3–5 times body weight) positively affect BMD [19]. Bone formation can also be altered by external agents such as certain metals, pesticides, and components in cigarette smoke [19].

To summarize, the normal, monthly occurrence of the female menstrual cycle represents an intricate interaction of three organs – hypothalamus, anterior pituitary, and ovaries – resulting in a feedback mechanism whereby several secreted hormones influence each other to effect maturation and ovulation of an egg (follicle). Next, the endometrium becomes prepared to receive the mature follicle and, if no implantation occurs, then sloughing of the uterine lining manifests itself by menstrual bleeding and the cycle repeats. Disturbances in any portion of this hormonal loop between the reproductive system and these two specific centers in the brain could, in turn, alter the quality/quantity of menstruation and secondarily affect bone deposition, especially during the critical time of initial peak bone mass acquisition involved with the pubertal/adolescent stage [152021].

7.3.3 Bone Composition, Physiology, Function, and Interaction with Ovarian Hormones

Skeletal tissue is one of the hardest and strongest tissues in the body. Bone is mineralized connective tissue comprised of specialized cells, along with noncellular substances, organic matrix (35 % by weight), and inorganic mineral (65 %). Two key types of bone cells are osteoblasts, which are involved in bone formation, and osteoclasts, which are involved in bone resorption. Components making up the organic matrix include glycoproteins, collagen (Type I), elastin, and protein (90 % collagen), bathing in a sea of gelatin-like mucopolysaccharide (ground substance). Bone can be classified into two categories: cortical, representing 80 % of bone mass, and trabecular, representing only 20 % of bone mass but comprising 80 % of bone surface area [19].

Collagen fibers in the bony skeleton represent specific sites where inorganic calcium/phosphate hydroxyapatite crystals are deposited prior to the mineralization process of bone. Ninety-eight to ninety-nine percent of the body’s total calcium is sequestered in the skeletal framework, which serves as a mineral bank and releases calcium into the bloodstream to keep serum calcium levels constant. Because the quantity of calcium is tightly regulated, the body will rob calcium from its main reservoir, bone, to maintain adequate blood levels in order to carry out essential, vital tasks such as blood clotting and muscle contraction [2422]. Calcium, however, cannot be absorbed and incorporated into bone unless vitamin D is readily available [211]. Ovarian hormones play an important role in the metabolism of calcium and vitamin D. Indeed, estrogen helps to regulate the absorption of calcium, subsequently contributing to bone formation, as already discussed above. In effect, any irregularities in the menstrual cycle will negatively affect bone deposition in the long run by negating estrogen’s positive influence on calcium balance. Additionally, with the loss of protection from estrogen, osteoclasts will be affected to a greater extent than osteoblasts, resulting in an uncoupling effect. This dissociation between osteoblasts and osteoclasts causes undesirable bone loss, which could manifest itself as early osteoporosis [492324] (Fig. 7.3).

A145875_2_En_7_Fig3_HTML.gif

Fig. 7.3

Bone remodeling

7.3.4 Peak Bone Mass

Peak bone mass (PBM) signifies the maximal quantity of bone which can be gained primarily during the adolescent years (with the critical window being between 9 and 20 years), while the skeleton is undergoing an accelerated growth in both size and density. By age 7, females have reached 80 % of their adult height but only 40 % of their PBM [2]. This “adolescent growth spurt” occurs 1–2 years preceding the rapid deposition of bone into the skeleton. In females, up to 90 % of PBM is accumulated by 18 years of age [310]. After this prime period, bone can still continue to grow in terms of strength and density, up until about age 25–35, at which time true PBM is reached [2325]. However, some researchers have shown that this PBM acquisition may occur as young as the late teens [7]. After attainment of peak bone mass, measures to maintain bone density are of paramount importance since physiologic bone loss will inevitably occur gradually over time [272526]. In fact, prior to reaching menopause in their fourth or fifth decade, females lose about 0.3 % of their entire skeleton each year after the final acquisition of peak bone mass [2] (Fig. 7.4).

A145875_2_En_7_Fig4_HTML.gif

Fig. 7.4

Rate of bone loss through a women’s lifetime (Fig 14.2 in Ist ed)

The quantity of bone deposited in the skeleton is influenced by both genetics (uncontrollable) and environmental (controllable) factors [37]. Mechanical loading in the form of weight-bearing/resistance exercise; appropriate and adequate nutrition ( i.e., sufficient consumption of key bone building nutrients such as calcium, magnesium, zinc, vitamins C and D); and normal, regular menses all contribute to optimal bone health [28101224]. Endocrine function is highly dependent on the amount of available energy. Energy availability is the quantity of energy remaining after physiological energy is utilized (i.e., energy for everyday movement and activity). As long as energy availability is maintained, the endocrine system will function optimally with normal hormone serum levels. However, without adequate energy the endocrine system is altered, primarily affecting the hypothalamic production of hormones [27]. Insufficient energy will adversely affect the pulsatile secretion of LH. This causes a decrease in hormones such as estrogen, testosterone, GH, and IGF-1. On the other end of the spectrum, an extreme excess of available energy, as seen in obesity, will tend to cause hormone level alteration as well [28]. In short, any aberrant serum levels of sex hormones will alter the menstrual cycle and ultimately affect bone balance [29].

A delay in menarche (initiation of menses), dysmenorrhea (irregular menstruation), oligomenorrhea (insufficient number of cycles per year), or amenorrhea (absence of menses) all will interfere with the final attainment of peak bone mass by causing more rapid bone loss. Bone mass density steadily declines, particularly in non-weight-bearing limbs, as the number of missed menses increases and this loss of BMD may not be completely reversible [25]. Irregular menses is primarily due to a deficiency of estrogen and, if not corrected promptly, ultimately will result in premature osteoporosis [230]. Such menstrual irregularities/disorders could be caused by various factors: extremely low weight, rapid weight loss, excessively intense exercise, and disordered eating, along with associated extreme physical and/or psychological stress [61631]. Specifically, women with menstrual disorders will lose as much as 2 % of their skeleton per year, almost tenfold more than the usual, natural rate. In other words, exercising excessively can negatively affect both the reproductive and the skeletal systems, altering the body’s normal hormonal milieu and causing a reduction in bone mass [32]. One study has found that total, vigorous, intense training for more than 8 h per week could lead to amenorrhea and, subsequently, osteoporosis with its inherent risks [18].

Physical activity affects the skeleton differently during the various stages of puberty [7]. Studies have shown that estrogen increases skeletal sensitivity to mechanical loading, suggesting that early and mid-puberty are optimal times for skeletal benefit as far as bony deposition is concerned [33]. Female athletes, particularly in sports such as running, gymnastics, and swimming, reach menarche later than non-athletes. A study conducted on sisters found menarche occurred later in swimmers than their sedentary siblings, thus may potentially affect bone mass negatively [28].

7.3.5 Results of an Abnormal Menstrual Cycle on Peak Bone Mass

Even though genetic factors significantly influence bone mass and density, other factors such as nutrition, exercise, disease, drugs, and age at menarche can play a role as well. Abnormal menses can be classified into two different categories. Primary amenorrhea is defined as the absence of menstruation by age 15 or within 5 years after breast development. Secondary amenorrhea is termed as the absence of three or more consecutive menses following menarche. It has been estimated that 1 in 5 active women have some form of abnormal menses [34].

As discussed above, insufficient quantity of available energy will cause altered endocrine function resulting in abnormal hormone levels, which in turn affect the menstrual cycle. Studies have found menstrual disorders occurring in 24–26 % of runners [35]. Loucks found that in females, after 5 days of low energy availability, there is a decrease in LH pulse frequency [36]. Similarly, the prevalence of amenorrhea increases from 3 to 60 % in long-distance runners as the weekly distance ran is increased from less than eight miles to over 70 miles [37]. The presence of altered menstruation in adult female athletes has been reported to range from 12 to 79 %, with adolescent athletes having even higher rates [4]. When facing the problem of irregular menses occurring in an adolescent female, causes for secondary amenorrhea should be identified such as pregnancy, endocrine disorders, anatomic defects, or tumors of the involved organs, which can interfere with the hypothalamic-pituitary-ovarian axis [7161825]. After these potential pathologic causative factors are excluded, then information regarding eating habits, weight control behavior, and exercise patterns should be obtained. This detailed history is used to evaluate whether the affected young patient is at risk for premature osteoporosis due to the female athlete triad (diagnosis of exclusion) – a constellation of amenorrhea, disordered eating, and osteoporosis. More importantly, it must be understood that the amount of bone which is lost may not be totally recovered, even upon resumption of normal menses [32].

Females at a higher risk for amenorrhea are usually involved in sports requiring an aesthetic/athletic look or those needing to weigh less for better performance (gymnasts, dancers, runners, divers, etc.) [6102938]. The afflicted female athlete’s young, fragile bones are at two- to threefold increased risk for stress and/or frank fractures, similar to older, perimenopausal women in their 40s and 50s, especially if the duration of absent menses is longer than 6 months [183038]. Bone mass density further declines as the number of missed menses increases [39]. Stress fractures are more common in female athletes with amenorrhea, with a relative risk of fracture four to five times greater in amenorrheic athletes [30]. However, there is a positive effect of certain types of weight-bearing exercise on bone density. Zanker et al. studied a group of retired female gymnasts and found they had higher BMD compared to women who did not exercise or participate in sports [40]. Even though involvement in a regular program of exercising, especially under high loads such as gymnastics, may partially offset the osteopenic bone caused by being amenorrheic, this is still far from being enough if an inadequate amount of calories is consumed. In fact, research has shown that bone mass in females who are sedentary, eat well, and have normal monthly cycles is actually higher than those athletes who exercise to the point of losing their menses [2]. Similarly, another study has shown that increases in circulating FSH levels above 20 mIU/L are linked to progressive bone loss in perimenopausal women, again stressing the importance of maintaining regular menstruation to preserve bone density [18].

Currently, dual energy x-ray absorptiometry (DEXA) is the “gold standard” for measurement of bone mineral density (BMD) to assess bone heath, and thus, it should be used to help diagnose osteoporosis and monitor progress of treatment [2101216242638]. This technique uses emission of x-rays at two separate energy levels to distinguish bone from the surrounding soft tissue with very low radiation exposure. The time for scanning with this type of device is brief and BMD measurements are more accurate (within 1–2 %) as compared to other methods [210]. If the DEXA scan result for BMD is between 1.0 and 2.5 standard deviations (SD) below the mean for young adults, then bone is considered osteopenic. Even at this level, there exists 2–2.5 times more risk of spine or hip fractures due to increased fragility of the skeleton. On the other hand, bone is deemed osteoporotic (with associated higher fracture risk) if the BMD is equal to or greater than 2.5 SD from the mean [2101626] (see Table 7.1). One study demonstrated that reduced urinary sex steroid hormones are found during the luteal phase of the menstrual cycle in premenopausal women with lower BMD (10th vs. 50th–75th percentile), again linking monthly menses to bone mass acquisition [19]. As an adjunct, other methods to assess bone metabolism include serum osteocalcin and alkaline phosphatase (for bone formation) and urine collagen breakdown products (telopeptide crosslinks) as indicators of resorption and current rate of bone loss, respectively [21012].

The next step in prevention of early onset of osteopenia/osteoporosis in an adolescent female is to correct any offending factor contributing to the rapid bone loss. First steps should include ensuring adequate and appropriate dietary intake of nutrition, reducing quantity of training (5–20 % less), increasing body weight slowly and gradually (generally 5 % of body weight increase or one-half to one pound per week), and, finally, conferring with her to confirm that she is maintaining the correct goal weight [63238]. Proper nutrient intake can greatly aid in the prevention of bone loss. The benefits of calcium supplementation have been shown to be more beneficial before the onset of puberty [41]. A study conducted on 8-year-old prepubertal girls found that by increasing the daily calcium dose from 700 to 1,400 mg, this can raise the BMD by 58 % compared to the placebo group after 1 year of supplementation [42]. Regulation of menses can be obtained by hormonal replacement therapy (HRT) – the oral contraceptive pill is a popular form of this type of pharmacological treatment [32]. However, the ultimate effectiveness of hormonal replacement remains controversial. Oral estrogen leads to suppression of GH and IGF-1 concentrations as already discussed above; these two hormones are very vital in bone development [36]. Specific lifestyle changes are recommended as well: avoidance of inactivity, refraining from cigarette smoking, and minimizing drinking alcohol [1]. In terms of dietary intake, avoid drinking caffeinated beverages and ingesting excess protein is recommended because both of these substances contribute to calcium wasting and, thus, could secondarily affect bone formation. Adequate intake of calcium and vitamin D will also aid in bone building. Finally, appropriate exercise is recommended, especially the weight-bearing type (loading in the erect, standing position) with at least some impact such as walking or jogging. As discussed previously, bone will build at points of mechanical stress (Wolff’s Law). However, the mode of exercise needs to be considered as not to overload the bone, causing injury and eventually skeletal failure [2391216192538]. Studies have shown that jumping is an activity sufficient to stimulate bone growth, because one jump produces two rapid strain energies (taking off and landing). The ground reaction force from landing and muscle activation with this type of maneuver has been shown to be enough of a stimulus for adequate bone growth [43].

Evaluation and treatment for females with menstrual disturbances include conducting a detailed history and physical exam, plus possibly ordering certain laboratory tasks. It is also prudent to approach management of the female at risk by compiling a multidisciplinary team, involving an internist to rule out chronic disease, a psychiatrist/psychologist to address associated eating disorders and other psychological issues, a gynecologist to rule out anatomic abnormalities and for prescribing HRT, a dietician for nutritional counseling, and an endocrinologist to address other possible pathology interfering with the hormonal feedback loop [1829]. Additionally, it is very important to involve family members, teachers, trainers, other players, and coaches to solicit additional support for the involved patient, ultimately to help regulate and maintain normal bodily functions in the female athlete [2930] (Fig. 7.1).

7.4 Future Directions and Concluding Remarks

The role of the female menstrual cycle in terms of its contribution toward acquisition of peak bone mass has been fairly well elucidated. A regular, well-functioning monthly cycle is of paramount importance in bone deposition during the adolescent growth spurt and then in prevention of bone loss after peak bone mass is achieved in the second decade of life. The main hormone involved in bone regulation is estrogen which is secreted by the ovaries, affecting both the osteoclasts and the osteoblasts, keeping these two types of bone cells in balance in terms of their function on skeletal resorption and formation, respectively. Additionally, the organs involved with controlling the menses are the hypothalamus, anterior pituitary and, of course, the ovaries. Each organ secretes different hormones, which interact in a complex, loop-type feedback mechanism to regulate the monthly female cycle, in order to maximize bone deposition and minimize bone loss. If menarche is delayed or if menstrual dysfunction occurs or menses disappears entirely, then the protective mechanism of estrogen on bone is lost. If this menstrual disturbance is not corrected fairly promptly, it will eventually result in osteopenia or frank osteoporosis, ultimately increasing one’s susceptibility to fractures. In fact, osteoporotic prevention starts as early as the initial onset of menarche during adolescence. Additionally, other factors, such as lifestyle habits (nutrition, training, etc.), also play a very essential part in contributing to bone building (formation) or bone loss [1825]. As such, measures taken to ensure that the monthly female menstrual cycle is functioning correctly and optimally are of utmost importance to positively influence the final attainment of peak bone mass [18].

References

1.

Elgan C, Dykes AK, Samsioe G. Bone mineral density changes in young women: a two year study. Gynecol Endocrinol. 2004;19(4):169–77.PubMedCrossRef

2.

Lane J, Russell L, Khan S. Osteoporosis. Clin Orthop Relat Res. 2000;March(372):139–50.CrossRef

3.

National Institutes of Health Osteoporosis and Related Bone Diseases-National Resource Center. Osteoporosis: peak bone mass in women, Mar 2005; URL: http://​www.​osteo.​org/​newfile.​asp?​doc=​r701i&​doctitle=​Peak+Bone+Mass+i​n+Women&​doc.

4.

Resnick D, Manolagas S, Niwayama G. Histogenesis, anatomy, and physiology of bone. Anatomy and physiology. Philadelphia: Saunders; 1989. p. 16–28.

5.

Perez-Lopez FR, Chedraui P, Lopez-Cuadros JL. Bone mass gain during puberty and adolescence: deconstructing gender characteristics. Curr Med Chem. 2010;17:453–66.PubMedCrossRef

6.

Clarke BL, Khosla S. Female reproductive system and bone. Arch Biochem Biophys. 2010;503:118–28.PubMedCrossRefPubMedCentral

7.

Brown S. Better bones at every age. Lets Live Magazine, Oct 2000.

8.

Lebrun C. Menstrual cycle dysfunction. American College of Sports Medicine, Oct 2000

9.

Nichols D, Bonnick S, Sanborn C. Bone health and osteoporosis. The Athletic Woman. 2000;19(2): 233–49.

10.

United States Department of Health and Human Services. Bone health and osteoporosis: a report of the surgeon general. Chapter 6: Determinants of bone health, Oct 2004; URL: http://​www.​surgeongeneral.​gov/​library/​bonehealth/​chapter_​6.​html.

11.

Lane JM, Nydick M. Osteoporosis: current modes of prevention and treatment. J Am Acad Orthop Surg. 1999;7(1):19–31.PubMed

12.

Altruis Biomedical Network. Anatomy and physiology. E-Gynecologic.com 2000; URL: http://​www.​e-gynecologic.​com/​index.​html.

13.

Guyton A, Hall J. Female physiology before pregnancy; and the female hormones. In: Schmitt W, Gruliow R, Faber P, Norwitz A, Shaw P, editors. Textbook of medical physiology. 10th ed. Pennsylvania: Saunders; 2001. p. 929–43.

14.

Berne R, Levy M, Koeppen B, Stanton B, editors. The reproductive glands. Physiology. 5th ed. St. Louis, MO: Mosby; 2004. p. 920–78.

15.

Harmon K. Evaluating and treating exercise-related menstrual irregularities. Phys Sportsmed. 2002;30(3):29–35.PubMed

16.

Khan A, Syed Z. Bone densitometry in premenopausal women: synthesis and review. J Clin Densitom. 2004;7(1):85–92.PubMedCrossRef

17.

Nelson L. Amenorrhea. eMedicine, May 2005. URL: http://​www.​emedicine.​com/​med/​topic117.​htm.

18.

Duncan CS, Blimki CJR, Cowell CT, Burke ST, Briody JN, Howman-Giles R. Bone mineral density in adolescent female athletes: a relationship to exercise type and muscle strength. Med Sci Sports Exerc. 2002;34:286–94.PubMedCrossRef

19.

Whiting WC, Zernicke RF. Biomechanics of musculoskeletal injury. Champaign, IL: Human kinetics; 1998.

20.

Csermely T, Halvax L, Schmidt E, Zambo K, Vadon G, Szabo I, et al. Occurrence of osteopenia among adolescent girls with oligo/amenorrhea. Gynecol Endocrinol. 2002;16(2):99–105.PubMedCrossRef

21.

Galuska DA, Sowers MR. Menstrual history and bone density in young women. J Womens Health Gend Based Med. 1999;8(5):647–56.PubMedCrossRef

22.

Altruis Biomedical Network. Osteoporosis. E-Gynecologic.com 2000; URL: http://​www.​e-gynecologic.​com/​index.​html.

23.

Thys-Jacobs S. Micronutrients and the premenstrual syndrome: the case for calcium. J Am Coll Nutr. 2000;19(2):220–7.PubMedCrossRef

24.

Templeton K. Secondary osteoporosis. J Am Acad Orthop Surg. 2005;13(7):475–86.PubMed

25.

Erickson S, Sevier T. Osteoporosis in active women: prevention, diagnosis, and treatment. Phys Sportsmed. 1997;25(11):61–72.PubMedCrossRef

26.

Theodorou S, Theodorou D, Sartoris D. Osteoporosis: a global assessment of clinical and imaging features. Orthopaedics. 2005;28(11):1346–53.

27.

Jayasinghe Y, Grover SR, Zacharin M. Current concepts in bone and reproductive health in adolescents with anorexia nervosa. BJOG. 2008;115(3):304–15.PubMedCrossRef

28.

Brooks GA, Fahey TD, Baldwin KM. Exercise physiology: human bioenergetics and its applications. 4th ed. New York, NY: McGraw-Hill; 2005.

29.

Women’s Health Orthopaedic Edition. Assessing health in young female athletes. 2000 November–December;3(6):205–7.

30.

Slemenda C, Longcope C, Peacock M, Hui S, Johnston C. Sex steroids, bone mass, and bone loss. J Clin Invest. 1996;97(1):14–21.PubMedCrossRefPubMedCentral

31.

Balasch J. Sex steroids and bone: current perspectives. Human Reprod Update. 2003;9(3):207–22.CrossRef

32.

Warren MP, Stiehl AL. Exercise and female adolescents: effects on the reproductive and skeletal systems. J Am Med Womens Assoc. 1999;54(3):115–20.PubMed

33.

Devlin MJ. Estrogen, exercise, and the skeleton. Evol Anthropol. 2011;20(11):54–61.PubMedCrossRef

34.

Beals KA, Hill AK. The prevalence of disordered eating, menstrual dysfunction, and low bone mineral density among US collegiate athletes. Int J Sport Nutr Exerc Metab. 2006;16(1):1–23.PubMed

35.

Sanborn CF, Albrecht BH, Wagner Jr WW. Athletic amenorrhea: lack of association with body fat. Med Sci Sport Exerc. 1987;19:207–12.

36.

Lissett CA, Shalet SM. The impact of dose and route of estrogen administration on the somatotropic axis in normal women. J Clin Endocrinol Metab. 2003; 88:4668–72.PubMedCrossRef

37.

Sanborn CF, Martin BJ, Wagner WW. Is athletic amenorrhea specific to runners? Am J Obstet Gynecol. 1982;143:859–61.PubMed

38.

Hobart J, Smucker D. The female athlete triad. Am Fam Physician. 2000;61(11):3357–64.PubMed

39.

Keen AD, Drinkwater BL. Irreversible bone loss in former amenorrheic athletes. Osteoporos Int. 1997; 7:311–5.PubMedCrossRef

40.

Zanker CL, Osborne C, Cooke CB, Oldroyd B, Truscott JG. Energy balance, bone turnover and menstrual history of sedentary female former gymnasts, aged 20–32. Osteoporos Int. 2004;15:145–54.PubMedCrossRef

41.

Johnston CC, Miller JZ, Slemenda CW, Resiter TK, Hui S, Christian JC, et al. Calcium supplementation and increases in bone mineral density in children. N Engl J Med. 1992;327:82–7.PubMedCrossRef

42.

Bonjour JP, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G, et al. Calcium enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. J Clin Invest. 1997;99:1287–94.PubMedCrossRefPubMedCentral

43.

Bailey CA, Brooke-Wavell K. Exercise for optimizing peak bone mass in women. Proc Nutr Soc. 2008; 67:9–18.PubMedCrossRef