At age 29.8 yr, in place of oral contraceptives, she was prescribed estradiol skin patches (Estraderm TTS 100; Novartis Pharmaceuticals UK Ltd., Camberley, UK) providing 100-μg estradiol per 24 h, to be given with and an oral progestogen, norethisterone (Micronor HRT; Janssen-Cilag Ltd., High Wycombe, UK) at a dose of 1 mg·d−1 for 12 consecutive days of a 28-d cycle. This treatment increased her measured serum estradiol concentration to between 300 and 400 pmol·L−1. She resumed her exercise regimen, and during the following 4 yr, her body mass declined by a further 0.8 kg. Nevertheless, annual DXA scans revealed a gradual increase of BMD at her lumbar spine that amounted to 9.4% (Table 1 and Fig. 1). There was no significant change of BMD at her proximal femur. At age 33.4 yr (BMI 14.8 kg·m−2; body fat content < 4.0%), a fasting serum sample revealed concentrations of nutritionally dependent hormones that were either below, or at the lower end of, the normal reference ranges for sex and age: IGF-1, 115 μg·L−1 (normal range: 120–280 μg·L−1), total T3, 98 ng·dL−1 (normal range: 84–208 μg·L−1) and leptin, <0.5 ng·mL−1 (normal range for women, BMI 20–25 kg·m−2: 15–20 ng·mL−1).
At age 33.5 yr, she made a personal decision to gain weight. This presented a physical and emotional challenge; however, she progressively increased her energy intake, primarily through the consumption of full-fat milk drinks between meals. She continued to exercise daily for 50–60 min and adhered to the prescribed estrogen-progestogen regimen. Her body mass increased gradually, by 8.1 kg over 36 months (BMI from 14.9 to 17.6 kg·m−2). A whole-body DXA scan revealed a 4.9-kg increase of body fat, a 3.2-kg increment of lean tissue, and an increase of percent body fat from <4.0% to 11.8% of total mass. Figure 2 illustrates the distribution of fat storage that accompanied the 6.1-kg increment of body mass between ages 34.6 and 36.9 yr. A consistent increase of BMD at her proximal femur was observed that amounted to 16.9% of her lowest recorded value at 32.8 yr (Table 1 and Fig. 1). Meanwhile, the BMD of her lumbar spine remained stable. She has continued to gain weight and has sustained no further fractures.
The subject of this case study displayed characteristic features of the “female athletic triad” as manifested by dietary restriction, a high level of physical activity, amenorrhea, and osteoporosis (25). She had begun to restrict her energy intake shortly after commencing regular training for distance running, in early puberty, and had sustained energy-restricting behaviors for over 20 yr. By the age of 29 yr, her osteoporosis was advanced and symptomatic.
This woman’s low BMD at her first DXA scan (age 24.8 yr) probably reflected an impaired acquisition of bone mass during childhood. In girls, normal pubertal progression is accompanied by a 30–50% increment of bone mass, with an attainment of a peak value within 4 yr postmenarche (2,36). The deleterious effects of energy restriction and gonadal suppression on the acquisition of bone mass during this phase of development are well documented (1,15,19). The very low BMD measured within this woman’s proximal femur (T-score −2.8) at age 24.8 yr contrasted with previous observations of the distribution of BMD within adult amenorrheic runners, which have reported a significantly reduced BMD at the lumbar spine (T-score −1 to −2), with either a normal, or marginal, reduction of BMD at the proximal femur (T-score > −1.0) (11,23,26). However, the amenorrheic runners of these previous studies had experienced shorter intervals of menstrual disturbance than our subject, their amenorrhea had generally been secondary rather than primary, and their BMI had usually exceeded 17.5 kg·m−2 (11,23,26). The distribution of BMD reported in our subject displayed a closer resemblance to that seen in women with anorexia nervosa, who usually show significant deficits of cortical as well as trabecular bone (1,15).
The most plausible explanation for the progressive reduction of BMD within this woman’s lumbar spine and total proximal femur from age 24.8 to 29.7 yr was a gradual loss of body mass (total, 3.7 kg) that lowered her BMI from 16.4 to 15.0 kg·m−2. Retrospective and short-term prospective studies (<2 yr) of changes of BMD in young women with anorexia nervosa suggest that trabecular and cortical bone loss accelerate when BMI falls below a “threshold” value, which is often in the order of 16–17 kg·m−2 (1,15). It is proposed that this “threshold” marks a turning point, below which bone turnover is uncoupled, as exemplified by reduced serum levels of markers of bone formation and an elevated urinary excretion of markers of bone resorption (1,16,38). The suggested stimuli for this uncoupling are endocrine disturbances that accompany energy restriction and a reduced BMI (16,19,37,39). These disturbances include a raised serum concentration of cortisol (9,24), with reduced serum concentrations of sex hormones (6,38), insulin-like growth factor I (IGF-1) (16,37), 3,5,3′ triiodothyronine (T3) (6,37), and leptin (33,34). Recent research suggests that a reduction of serum IGF-1 concentration is particularly pertinent, because of a strong link between the magnitude of reduction of the serum concentration of IGF-1 and markers of bone formation under conditions of energy restriction (16,19,38,39). At age 33.4 yr, our subject displayed subnormal serum concentrations of IGF-1, leptin, and T3, which concurs with previous observations in women with the female athlete triad (33,38). It is also noteworthy she had discontinued her running training at age 25 yr yet persisted to expend large amounts of energy through the practice of mainly nonweight-bearing or low-impact activities. This practice would tend to contribute to a negative energy balance without offering an osteogenic stimulus.
The influence of oral contraceptives on the acquisition and maintenance of bone mass in young women is currently debatable (3). The few controlled trials that have investigated the efficacy of these drugs for the protection of bone mass in active, underweight women with amenorrhea have produced equivocal findings, with the majority indicating little benefit (10,12,14,19,22). Of importance, is that recent research suggests that oral contraceptive use in adolescence and early adulthood may impair bone gain, or induce untimely bone loss, even when combined with regular exercise (5,37). Consequently, it is possible that the sustained use of oral contraceptives by our subject had a detrimental rather than a beneficial effect on her bone mass.
An interesting observation in this study was an increase of BMD within the lumbar spine during treatment with estradiol skin patches and oral norethisterone. This increase occurred in the absence of weight gain and was recorded using the same absorptiometer. To date, there have been no published trials of the skeletal effects of estradiol administered by the transdermal route in women with the female athlete triad or with anorexia nervosa. However, such treatment has been shown to induce significant gains of bone mass at the lumbar spine in other estrogen deficient states (7,13). There is also evidence to suggest that the progestogen norethisterone exerts an anabolic action in bone (4). To attempt to explain the apparent positive influence of estradiol skin patches on BMD within this woman’s lumbar spine is beyond the scope of the present study. Nevertheless, it was noted that this treatment greatly increased her serum estradiol concentration (to between 300 and 400 pmol·L−1). Although speculative, it is possible that very lean and active women require a higher circulating concentration of estradiol to preserve bone mass than sedentary women with greater stores of body fat. Previous research has shown that a paucity of body fat and endurance exercise both appear to favor the metabolism of endogenous estrone, via 2-hydroxylation, to catechol-estrogens with antiestrogenic properties (30). Concomitantly, the synthesis of biologically active estriol (via the 16α-hydroxylase pathway) is reduced. On this premise, the administration of high doses of exogenous estradiol may be required to mediate an anabolic effect in responsive tissues (17).
The substantial increase of BMD measured within this woman’s total proximal femur with progressive weight gain was recorded using the same absorptiometer. This finding is consistent with observations made in previous studies of women recovering from the female athlete triad or anorexia nervosa (8,15,18,19,35). These previous studies also showed that significant increments of bone mass accompany weight gain even before the resumption of regular menses. It is of interest that repeated, whole-body DXA scans of our subject illustrated a preferential gain of fat mass within the femoral region. Adipocytes within this region possess a high capacity for leptin synthesis in estrogen replete women (21,29). The possible implications of these observations are that leptin appears to act both locally and systemically to increase bone formation, by enhancing the differentiation of marrow stromal cells to osteoblasts (32). Consequently, it might be speculated that the pattern of fat storage with weight gain in this woman assisted a site-specific increase of BMD.
1. Audi, L., D. M. Vargas, M. Gussinye, D. Yeste, G. Marti, and A. Carrascosa. Clinical and biochemical determinants of bone metabolism and bone mass in adolescent female patients with anorexia nervosa. Pediatr. Res. 51: 497–504, 2002.
2. Bailey, D. A., H. A. Mckay, R. L. Mirwald, P. R. Crocker, and R. A. Faulkner. A six year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the University of Saskatchewan bone mineral accrual study. J. Bone Miner. Res. 14: 1672–1679.
3. Bennell, K., S. White, and K. Crossley. The oral contraceptive pill: a revolution for sportswomen? Br. J. Sports Med. 33: 231–238, 1999.
4. Berenson, A. B., C. M. Radecki, J. J. Grady, V. I. Rickert, and A. Thomas. A prospective controlled study of the effects of hormonal contraception on bone mineral density. Obstet. Gynecol. 98: 576–582, 2001.
5. Burr, D. B., T Yoshikama, D. Teegarden, et al. Exercise and oral contraceptive use suppress the normal age-related increase in bone mass and strength of the femoral neck in women 18–31 years of age. Bone 27: 855–863, 2000.
6. DE Souza, M. J., and D. A. Metzger. Reproductive dysfunction in amenorrheic athletes and anorexic patients: a review. Med. Sci. Sports Exerc. 23: 995–1007, 1991.
7. Delmas, P. D., B. Pornel, D. Felsenberg, et al. Three-year follow-up of the use of transdermal 17beta-estradiol matrix patches for the prevention of bone loss in early postmenopausal women. Am. J. Obstet. Gynecol. 184: 32–40, 2001.
8. Drinkwater, B. L., K. Nilson, S. Ott, C. H., and Chesnut, III. Bone mineral density after resumption of menses in amenorrheic athletes. JAMA 256: 380–382, 1986.
9. Gold, P. W., H. Gwirtsman, and P. C. Avgerinos. Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. N. Engl. J. Med. 314: 1335–1342, 1986.
10. Golden, N. H., L. Lanzkowsky, J. Schebendach, C. J. Palestro, M. S. Jacobson, and I. R. Shenker. The effect of estrogen
-progestin treatment on bone mineral density in anorexia nervosa. J. Pediatr. Adolesc. Gynecol. 15: 135–143, 2002.
11. Gremion, G. R., D. Rizzoli, G. Slosman, G. Theintz, and J. P. Bonjour. Oligo-amenorrheic long-distance runners may lose more bone in spine than femur. Med. Sci. Sports Exerc. 33: 15–21, 2001.
12. Grinspoon, S., L. Thomas, K. Miller, D. Herzog, and A. Klibanski. Effects of recombinant human IGF-1 and oral contraceptive administration on bone density in anorexia nervosa. J. Clin. Endocrinol. Metab. 87: 2883–2891, 2002.
13. Gussinye, M., P. Terrades, D. Yeste, E. VICENS-Calvert, and A. Carrascosa. Low areal bone mineral density in adolescents and young adult Turner syndrome patients increase after long-term transdermal estradiol therapy. Horm. Res. 54: 131–135, 2000.
14. Hergenroeder, A. C., E. O. Smith, B. Shypailo, R. L. A. Jones, W. J. Klish, and K. Ellis. Bone mineral changes in young women with hypothalamic amenorrhea
treated with oral contraceptives, medoxyprogesterone, or placebo over 12 months. Am. J. Obstet. Gynecol. 176: 1017–1025, 1997.
15. Hotta, M., T. Shibasaki, K. Sato, and H. Demura. The importance of body weight history in the occurrence and recovery of osteoporosis
in patients with anorexia nervosa: evaluation by dual X-ray absorptiometry and bone metabolic markers. Eur. J. Endocrinol. 139: 276–283, 1998.
16. Hotta, M., I, Fukuda, K. Sato, N. Hizuka, T. Shibasaki, and K. Takano. The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels inpatients with anorexia nervosa. J. Clin. Endocrinol. Metab. 85: 200–206, 2000.
17. Hoyland, J. A., C. Baris, L. Wood, et al. Effect of ovarian steroid deficiency on estrogen
receptor alpha expression in bone. J. Pathol. 188: 294–303, 1999.
18. Jonnavithula S., M. P. Warren, R. P. Fox, and M. I. Lazaro. Bone density is compromised in amenorrheic women despite return of menses: a 2-year study. Obstet. Gynecol. 81: 669–674, 1993.
19. Klibanski, A., B. M. K. Biller, D. A. Schoenfeld, D. B. Herzog, and V. C. Saxe. The effects of estrogen
administration on trabecular bone loss in young women with anorexia nervosa. J. Clin. Endocrinol. Metab. 80: 898–904, 1995.
20. Lanyon, L. E. Control of bone architecture by functional load bearing. J. Bone Miner. Res. 7: S369–S375, 1992.
21. Montague, C. T., J. B. Prins, L. Sanders, J. E. Digby, and S. O’Rahilly. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 46: 342–347, 1997.
22. Munoz, M. T., G. Morande, J. A. Garcia-Centenera, F. Hervas, J. Pozo, and J. Argente. The effects of estrogen
administration on bone mineral density in adolescents with anorexia nervosa. J. Clin. Endocrinol. Metab. 146: 45–50, 2002.
23. Myburgh, K. H., L. K. Bachrach, B. Lewis, K. Kent, and R. Marcus. Low bone mineral density at axial and appendicular sites in amenorrheic athletes. Med. Sci. Sports Exerc. 25: 1197–1202, 1993.
24. Newman, M. M, and K. A. Halmi. Relationship of bone mineral density to estradiol and cortisol in anorexia nervosa and bulimia. Psych. Res. 29: 105–112, 1989.
25. Otis, C. L., B. Drinkwater, M. Johnson, A. Loucks, and J. Wilmore. American College of Sports Medicine position stand: the female athlete triad. Med. Sci. Sports Exerc. 29: i–ix, 1997.
26. Pettersen, U., B. Stalnacke, G. Ahlenius, K. Henrikkson-Larsen, and R. Lorentzon. Low bone mineral density at multiple skeletal sites, including the appendicular skeleton in amenorrheic runners. Calcif. Tissue Int. 64: 117–125, 1999.
27. Proctor, K. L., W. C. Adams, J. D. Shaffrath, and M. D. Van Loan. Upper limb bone mineral density of female collegiate gymnasts versus controls. Med. Sci. Sports Exerc. 34: 1830–1835, 2002.
28. Rencken, M. L., C. H. ChesnutIII, and B. L. Drinkwater. Bone density at multiple skeletal sites in amenorrheic athletes. JAMA 276: 238–240, 1996.
29. Roemmich, J. N., P. A. Clark, S. S. Berr, et al. Gender differences in leptin levels during puberty are related to the subcutaneous fat depot and sex steroids. Am. J. Physiol. 275: 43–51, 1998.
30. Snow, R. C., R. L. Barbieri, R. E. FRISCH. Estrogen
2-hydroxylase oxidation and menstrual function among elite oarswomen. J. Clin. Endocrinol. Metab. 69: 369–376, 1989.
31. Taaffe, D. R., C. Snow-Harter, D. A. Connolly, T. L. Robinson, M. D. Brown, and R. Marcus. Differential effects of swimming versus weight-bearing activity on bone mineral status of eumenorrheic athletes. J. Bone Miner. Res. 10: 586–593, 1995.
32. Thomas, T., F. Gori, S. Khosla, M. D. Jensen, B. Burguera, and B. L. Riggs. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 140: 1630–1638, 1999.
33. Thong, F. S, and T. E. Graham. Leptin and reproduction: is it a critical link between adipose tissue, nutrition and reproduction? Can. J. Appl. Physiol. 24: 317–336, 1999.
34. Warren, M. P., F. Voussoughian, E. B. Geer, E. P. Hyle, C. L. Adberg, and R. H. Ramos. Functional hypothalamic amenorrhea
: hypoleptinemia and disordered eating. J. Clin. Endocrinol. Metab. 84: 873–877, 1999.
35. Warren, M. P., J. Brooks-Gunn, R. P. Fox, C. C. Holderness, E. P. Hyle, and W. G. Hamilton. Osteopenia in exercise-associated amenorrhea
using ballet dancers as a model: a longitudinal study. J. Clin. Endocrinol. Metab. 87: 3162–3168, 2002.
36. Weaver, C. M. Adolescence: the period of dramatic bone growth. Endocrine 17: 43–48, 2002.
37. Weaver C. M., D. Teegarden, R. M. Lyle, et al. Impact of exercise on bone health and contraindication of oral contraceptive use in young women. Med. Sci. Sports Exerc. 33: 873–880, 2001.
38. Zanker, C. L., and I. L. Swaine. Bone turnover in amenorrhoeic and eumenorrhoeic women distance runners. Scand. J. Med. Sci. Sports 8: 20–26, 1998.
39. Zanker, C. L., and I. L. Swaine. Responses of bone turnover markers to repeated endurance running
under conditions of energy balance or energy restriction
. Eur. J. Appl. Physiol. 83: 434–440, 2000.