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by Karen K. Miller, M.D.
NEPTCC Newsletter MGH Neuroendocrine Center Bulletin Vol 8, Issue 1, Fall/Winter 2002
Part I - Amenorrheic Bone Loss
Although bone loss is most prevalent in post-menopausal women, some young women are also at high risk. Those with estrogen deficiency and chronic systemic illnesses and those taking medications that result in bone loss are most vulnerable (Table 1). Part I of this article will review amenorrheic bone loss, which often occurs in association with neuroendocrine disorders. Part II will focus on other causes of bone loss in women of reproductive age. Diagnosing bone loss in young women is not only important because of increased fracture risk incurred in the short-term, but also because it results in their entering menopause with reduced bone mass, putting them at much higher risk for fractures later in life.
Table 1. Causes of Bone Loss
in Women of Reproductive Age
- Estrogen Deficiency
- Acquired GnRH deficiency
- Hyperprolactinemia
- Functional hypothalamic amenorrhea
- (excessive exercise, stress, weight change)
- Anorexia nervosa
- Organic sellar or CNS disease
- Iatrogenic (surgery or radiation)
- Acquired gonadotropin deficiency
- Organic sellar or CNS disease
- Iatrogenic (surgery or radiation)
- Ovarian failure
- Oophorectomy
- Autoimmune
- Chemotherapy
- Idiopathic
- Medications
- GnRH agonists
- Depot medroxyprogesterone acetate
- Medication-induced
- Chronic glucocorticoid therapy
- Cyclosporine A
- Anti-convulsants
- Heparin
- Systemic Illnesses
- Cushing's syndrome
- Growth hormone deficiency
- Hyperparathyroidism
- Chronic liver disease
- Celiac sprue
- Inflammatory Bowel Disease
- Cystic Fibrosis
Amenorrheic Bone Loss
Estrogen deficiency in premenopausal amenorrheic women results in bone loss. In contrast, women with polycystic ovary syndrome, who have amenorrhea, but not reduced levels of gonadal steroids, have been found to have normal or even increased bone mineral density. There are a number of causes of hypoestrogenemic amenorrhea that result in bone loss. Acquired deficiency of the hypothalamic hormone gonadotropin releasing hormone (GnRH) occurs in patients with hyperprolactinemia, functional hypothalamic amenorrhea, anorexia nervosa, and hypothalamic or pituitary lesions. Hyperprolactinemia was the first cause of secondary hypogonadism to be identified as associated with bone loss 1. A 17 percent decrease in cortical and 15 to 30 percent decrease in trabecular bone mineral density have been reported in women with hyperprolactinemia 1-4.
Women with regular menstrual periods despite hyperprolactinemia do not incur bone loss, while their amenorrheic counterparts develop osteopenia despite similar elevations in serum prolactin levels 5. In addition, duration of amenorrhea is strongly associated with diminishing bone density, resulting in lower bone density in women with longer amenorrhea 6. Hypogonadism is, therefore, the likely mechanism of the bone loss in these young women, not the hyperprolactinemia itself. Functional hypothalamic amenorrhea due to excessive exercise, stress or weight loss also causes bone loss in women of reproductive age. Although weight-bearing exercise has been shown to increase bone density at weight-bearing skeletal sites, exercise sufficiently excessive to result in amenorrhea paradoxically results in bone loss. The female athlete triad, defined as amenorrhea, disordered eating behavior, and osteoporosis, has been increasingly recognized as a public health problem, particularly in college athletes.
Figure 1. Relationship between age at menarche and the percentage of ballet dancers studied with fractures. Reprinted from the New England Journal of Medicine with permission from the Massachusetts Medical Society [8].
Three to 66 percent of female athletes are amenorrheic, depending upon the type, intensity and duration of exercise, and the athlete's nutritional status. Amenorrheic athletes are at significant risk for bone loss. Drinkwater et al. compared amenorrheic athletes to eumenorrheic athletes of similar age, weight, percent body fat, height, age of menarche, sport and training schedule. The mean lumbar spine bone density of the amenorrheic athletes was 14 percent lower than their eumenorrheic colleagues 7. The mean vertebral bone density in the amenorrheic athletes, with a mean age 25 years, was equivalent to that of an average 51-year-old woman. Importantly, this reduced bone density puts these amenorrheic athletes at increased risk for fractures. Warren et al. studied 75 professional ballet dancers, ages 18 to 36 years, and found that the incidence of stress fractures was twice as high among amenorrheic dancers than in those with regular periods 8. In a study of 17 elite long distance runners, two-thirds of amenorrheic runners were found to have stress fractures, many at multiple sites. In contrast, only one of the eumenorrheic runners experienced a stress fracture 9. Delayed menarche as a result of excessive exercise results in striking vulnerability to stress fractures. Warren et al. demonstrated a linear relationship between age of menarche and prevalence of fractures in a group of ballet dancers. Delay of menarche to age 18 was associated with a nearly 90 percent risk for fractures (Figure 1) 8. Such interference with the normal pattern of gonadal steroidogenesis during puberty, during which approximately 90 percent of peak bone mass is formed, may therefore have particularly severe consequences on bone health.
One-third of women who have functional hypothalamic amenorrhea, such as related to simple weight loss, have vertebral bone densities of 2 standard deviations or more below the mean 10. Similarly, patients with hypothalamic or pituitary dysfunction from organic causes, such as radiation or surgery, with resultant estrogen deficiency due to GnRH or gonadotropin deficiency are also at risk for bone loss.
Anorexia nervosa results in much more severe bone loss than hypothalamic amenorrhea of other causes (Figure 2) 11, likely due to the effects of undernutrition directly on bone and on hormonal factors, such as insulin-like growth factor-I (IGF-I). The mean bone density in women with anorexia nervosa is two standard deviations below the age-matched mean 12. In fact, bone density in many young women with anorexia nervosa is commonly comparable to that post-menopausal women in their 70's or 80's 10. This bone loss has potentially severe lifetime consequences. Rigotti et al. demonstrated a seven-fold increase in the risk of sustaining a non-spinal fracture compared with age-matched young women 13. Further, although bone density may increase with weight gain and resumption of menses, significant reduction in bone density may persist, increasing the risk for fractures in later life.
Medications that induce estrogen deficiency also result in osteopenia in women of reproductive age. These include GnRH agonists, which may be used to treat severe endometriosis or uterine myomas. GnRH agonist therapy has been shown to result in reduced spinal bone density after six months of therapy. The use of "add-back" norethindrone (10 mg/daily), norethisterone (1.2 mg/daily), or post-menopausal doses of estrogen replacement therapy plus medroxyprogesterone may reduce or prevent bone loss 14. However, these "add-back" regimens may also reduce the effectiveness of the GnRH agonist therapy. Long-term use of depot medroxyprogesterone acetate may also result in bone loss, presumably by causing estrogen deficiency. Cundy et al. compared spinal bone densities in 200 women using depot medroxyprogesterone acetate for contraception with those of 350 healthy controls of reproductive age and found significantly reduced bone density in the depot medroxyprogesterone acetate users. In addition, women who had used the medication for more than 15 years, or who had begun using it before the age of 21, had lower bone densities than women who had used it for a shorter duration15. These results suggest that duration of use may be important and that there may be a dose-response phenomenon.
Ovarian Failure
The onset of menopause in young women results in similar effects on bone as when the onset is later in life. Significant bone loss has been demonstrated in women with a history of surgical oophorectomy as well as with premature ovarian failure from other causes, including autoimmune disease, chemotherapy or idiopathic. Cann et al. demonstrated a 21 percent reduction in mean spine bone density in women with premature ovarian failure compared with age-matched controls with regular menstrual periods 2. As increasing numbers of young women undergo chemotherapy and survive into older age, this is likely to become an increasingly important public health issue.
Diagnosis
Although bone density testing is not recommended routinely for pre-menopausal women, it should be performed in women at risk for bone loss. In these patients, baseline bone density scans are indicated to assess bone density and risk for fractures. Annual follow-up scans to determine the trend in bone density over time and the effectiveness of therapy are also important. This is true even in women with normal bone densities at baseline, who may have sustained an unmeasured decline from an even higher level. Measurement of AP lumbar spine bone density is often most useful, because most metabolic diseases have a greater effect on trabecular than cortical bone. In addition, spinal bone density measurements have the greatest precision. Therefore, changes in bone density over time can be detected earlier at this site.
Figure 2. The T scores for lumbar and total hip bone densities in normal controls (white; n = 30) and patients with HA (hatched; n = 19) and AN (black; n = 30). , P less than0.01 vs. controls; §, P less than0.001 vs. controls; , P less than 0.0001 vs. controls; §§, P less than 0.001 vs. HA; , P less than 0.0001 vs. HA. Results are the mean ± SEM. Reprinted from the Journal of Clinical Endocrinology and Metabolism with permission from the Endocrine Society [11].
Therapy
Estrogen therapy has been shown to be effective in women with premature ovarian failure. One small placebo-controlled study also suggests that estrogen therapy may be effective in normal-weight women with functional hypothalamic amenorrhea 16. However, definitive data are lacking. In contrast, estrogen therapy is ineffective in some forms of amenorrheic bone loss, and is contraindicated in others. For example, in a randomized trial, Klibanski et al. demonstrated that estrogen therapy is largely ineffective in women with bone loss from anorexia nervosa 17. In addition, retrospective studies have shown that women with anorexia nervosa who have used estrogen in the past or are currently using estrogen do not have higher bone densities than those who have never used estrogen. The lack of effectiveness of estrogen in this population may be due to the overriding effects of undernutrition on bone health. In other groups, for example women with histories of breast cancer who have chemotherapy-induced hypoestrogenemic amenorrhea, estrogen therapy is contraindicated, and studies are underway to determine whether other therapies, such as bisphosphonates, are effective.
Bisphosphonates should be used with caution in women of reproductive age and only in those with severe bone loss. It is not known whether they are safe in pregnancy nor whether bisphosphonates secreted into breast milk are detrimental to nursing infants.
In women receiving GnRH agonist therapy, add-back gonadal steroid regimens have been shown to reduce or even prevent bone loss. However, they may reduce the effectiveness of the GnRH agonist therapy in treating conditions such as endometriosis. Intermittent PTH administration has also been shown to be effective in increasing bone density in this population 18. However, it is investigational and, in high doses, causes osteosarcomas in rodents. Therefore, the safety of long-term use or use in young women has not been established.
Conclusion
Measurement of bone density is indicated in young women at risk for bone loss secondary to hypoestrogenemic amenorrhea. This includes patients with functional hypothalamic amenorrhea, anorexia nervosa, hyperprolactinemia, and pituitary or hypothalamic lesions. In addition, a number of medications that induce hypoestrogenemia, including GnRH agonists and depot medroxyprogesterone cause bone loss. Bone loss during puberty can have particularly severe consequences because of its deleterious impact on the development on peak bone density. In addition, women who experience bone loss during their reproductive years enter menopause with reduced bone density and increased fracture risk. Therefore, early intervention, when safe and effective therapies are available, is critical.
References
- Klibanski A, Neer R, Beitins I, Ridgway C, Zervas N, McArthur J. Decreased bone density in hyperprolactinemic women. N Eng J Med 1980; 303:1511-4.
- Cann C, Martin M, Genant H, Jaffe R. Decreased spinal mineral content in amenorrheic women. JAMA 1984; 251:626-9.
- Koppelman M, Kurtz D, Morrish K, et al. Vertebral body bone mineral content in hyperprolactinemic women. J Clin Endocrinol Metab 1984; 59:1050-3.
- Schlechte J, el-Khoury G, Kathol M, Walkner L. Forearm and vertebral bone mineral in treated and untreated hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1987; 64:1021-6.
- Klibanski A, Biller BMK, Rosenthal DI, Schoenfeld DA, Saxe V. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988; 67:124-130.
- Klibanski A, Greenspan SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med 1986; 315:542-546.
- Drinkwater B, Nilson K, Chesnut C, 3rd, Bremner W, Shainholtz S, Southworth M. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 1984; 311:277-81.
- Warren M, Brooks-Gunn J, Hamilton L, Warren L, Hamilton W. Scoliosis and fractures in young ballet dancers. Relation to delayed menarche and secondary amenorrhea. N Engl J Med 1986; 314:1348-53.
- Marcus R, Cann C, Madvig P, et al. Menstrual Function and Bone Mass in Elite Women Distance Runners. Ann Int Med 1985; 102:158-163.
- Biller BMK, Coughlin JF, Saxe V, Schoenfeld D, Spratt DI, Klibanski A. Osteopenia in women with hypothalamic amenorrhea: a prospective study. Obstetrics and Gynecology 1991; 78:996-1001.
- Grinspoon S, Miller K, Coyle C, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 1999; 84:2049-2055.
- Grinspoon S, Thomas E, Pitts S, et al. Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Ann Int Med 2000; 133:1-5.
- Rigotti NA, Neer RM, Skates SJ, Herzog DB, Nussbaum SR. The clinical course of osteoporosis in anorexia nervosa. JAMA 1991; 265:1133-1138.
- Surrey E, Judd H. Reduction of vasomotor symptoms and bone mineral density loss with combined norethindrone and long-acting gonadotropin-releasing hormone agonist therapy of sympotmatic endometriosis: a prospective randomized trial. J Clin Endocrinol Metab 1992; 75;558-563.
- Cundy T, Cornish J, Roberts H, Elder H, Reid I. Spinal bone density in women using depot medroxyprogesterone contraception. Obstet Gynecol 1998; 92.
- Hergenroeder A, O'Brian Smith E, Shypailo R, Jones L, Klish W, Ellis K. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol 1997; 176:1017-25.
- Klibanski A, Biller BMK, Schoenfeld DA, Herzog DB, Saxe VC. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metabolism 1995; 80:898-904.
- Finkelstein J, Klibanski A, Arnold A, Toth T, Hornstein M, Neer R. Prevention of estrogen deficiency-related bone loss with human parathyroid hormone-(1-34): A randomized controlled trial. JAMA 1998; 280:1067-1073.
* NEW PULLOUT FEATURE *
~ PATIENT GUIDE ~
The Neuroendocrine and Pituitary Tumor Clinical Center is initiating a new patient education feature which will appear from time to time in this Bulletin. These will consist of a separate pullout section which can be reproduced and handed out to patients who have questions about the topic being addressed.
This issue includes "Frequently Asked Questions About Transsphenoidal Surgery For Pituitary Adenomas - A Patient Guide." Authored by Brooke Swearingen, M.D., the renowned expert pituitary surgeon at Massachusetts General Hospital, it answers the 15 most commonly asked questions by patients requiring transsphenoidal surgery for pituitary adenomas.
