Amenorrheic Bone Loss1

Karen K. Miller and Anne Klibanski

Neuroendocrine Unit, Department of Medicine, Clinical Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 457B, Boston, Massachusetts 02114.


    Introduction
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
THE ASSOCIATION between postmenopausal estrogen deficiency and osteoporosis has been clearly established for many decades. In addition, congenital disorders causing estrogen deficiency, such as Turner’s syndrome or Kallman’s syndrome, may affect bone mineralization. The deleterious effects of acquired functional estrogen deficiency on bone metabolism in young women has only more recently been recognized. Secondary amenorrhea is a common disorder, and more than 4% of premenopausal women experience episodes of amenorrhea lasting more than 3 months (1). Estrogen deficiency in approximately 55% of these women is attributable to hypothalamic amenorrhea, a state of acquired GnRH dysregulation, including hyperprolactinemia, which induces a state of functional menopause. (2) In addition, premature ovarian failure due to autoimmune disease or secondary to chemotherapy is increasingly diagnosed.

The effects of estrogen deficiency on bone are characterized by an acceleration of bone turnover with a disproportionate augmentation of resorption compared with formation (3). Trabecular bone is typically affected more than cortical. Although the precise means by which estrogen deficiency causes increased bone turnover is not known, possible mechanisms include a direct effect on osteoblasts via estrogen receptors (4, 5, 6, 7); increased osteoclastic activity due to local bone-resorbing cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor (8, 9, 10, 11, 12, 13, 14, 15); and an increased skeletal vulnerability to the effects of PTH (16). This review will focus on the pathophysiology of osteoporosis associated with premenopausal estrogen deficiency in women with secondary amenorrhea (Table 1Go).


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Table 1. Causes of amenorrheic bone loss

 

    Acquired GnRH deficiency
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
Hyperprolactinemia, excessive exercise, stress, undernutrition, and anorexia nervosa are all causes of functional acquired GnRH deficiency and are associated with osteopenia. Functional GnRH deficiency is characterized by a wide spectrum of disordered GnRH secretion leading ultimately to ovarian dysfunction and deficiency of gonadal steroids. The most prevalent pattern of GnRH secretion, as demonstrated by frequent LH sampling, is a reduced frequency of pulsations (17). However, several other patterns of GnRH pulsatility have been documented and include frank apulsatility, recapitulation of puberty with pulsation occurring at night only (documented in some women with anorexia nervosa), decreased pulse amplitude, and a pattern of pulses seen normally in the early follicular phase (17, 18, 19). These disparate pulsatility patterns all result in a lack of folliculogenesis, progression to anovulation, and consequent gonadal steroid deficiencies resulting in osteopenia. In other women with organic sellar or central nervous system disease, including pituitary tumors and radiation damage, structural abnormalities may be present affecting GnRH and/or gonadotropin secretion. Finally, the use of GnRH agonists for the treatment of endometriosis, uterine fibroids, and other disorders has resulted in iatrogenically induced estrogen deficiency.


    Hyperprolactinemia
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
Hyperprolactinemic amenorrhea was the first identified model of functional hypogonadal osteoporosis and is associated with a 17% decrease in cortical (20) and a 15–30% decrease in trabecular (21, 22, 23) bone density. The importance of estrogen deficiency in the pathogenesis of bone loss in these young women was demonstrated by Klibanski et al., who showed that spinal bone mass was significantly lower in amenorrheic hyperprolactinemic women than that in their eumenorrheic counterparts despite similar elevations in PRL levels (24). In addition, patients with a longer duration of amenorrhea tend to have lower bone density (25). Factors other than menstrual status also contribute to the pathogenesis of bone loss in this population. As has been suggested in studies of women with premature menopause, obesity may be protective against osteopenia. In one study, a small subgroup of hyperprolactinemic amenorrheic women, 120–125% of ideal body weight, had normal cortical bone density, although their thinner counterparts demonstrated significant bone loss (25). Moreover, a significant correlation between spinal bone density and serum dehydroepiandrosterone sulfate levels has been reported in hyperprolactinemic women and raises the possibility that adrenal androgens play a role in the maintenance of normal bone mass in women (24).

If untreated, bone loss progresses in patients with hyperprolactinemic amenorrhea. Biller et al. found that spinal bone density decreased significantly in a group of hyperprolactinemic women who remained amenorrheic over a period of 1.7 ± 0.2 (±SEM) yr and resulted in a bone density more than 2 SD below the control mean in 42% of the group. However, restoration of normal menstrual function with dopamine agonist therapy results in an increase in bone density in most, but not all, women treated (Fig. 1Go) (26). The largest increases in bone density occur during the first 6–12 months of therapy, and bone density may not return to normal, even after several years of normal menstrual function (25, 26). Therefore, a significant number of women with a history of hyperprolactinemic amenorrhea may enter the menopause with preexisting osteopenia. These data support the hypothesis that a history of amenorrhea may be associated with a permanent increased fracture risk despite resumption of menses. The finding of osteopenia in these young women established amenorrhea as an important indication for lowering PRL levels sufficiently to restore ovulation. If dopamine agonist therapy is not effective or not tolerated, estrogen therapy or surgery can be considered. Estrogen has been shown to increase PRL messenger ribonucleic acid transcription in vitro (27, 28) and, in the setting of pregnancy, has been shown to increase prolactinoma size in a small subset of patients with microadenomas and in up to 15.5% of patients with macroadenomas (29). However, these data demonstrated an increase in tumor size in the setting of endogenous estrogen levels during pregnancy that are severalfold higher than those in nonparous women. Preliminary data have not shown a deleterious effect of estrogen replacement on tumor size in young amenorrheic women treated with estrogen replacement (30). However, the long term effects of estrogen replacement on hyperprolactinemic women with microadenomas remain unknown at this time.



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Figure 1. Bone density of the radial shaft in 32 women with hyperprolactinemic amenorrhea. Values for group 1 patients are shown before and after treatment for hyperprolactinemia; the solid bars represent the mean bone density, which increased significantly (P < 0.001) after treatment. Values for group 2 patients are shown before and after longitudinal follow-up without therapy; bone density decreased significantly (P < 0.002) in this group. (Reprinted with permission from New England Journal of Medicine, 315:544, 1986.)

 

    Hypothalamic amenorrhea
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
Functional hypothalamic amenorrhea due to excessive exercise or stress has been demonstrated to be associated with a reduction in trabecular and, to a lesser degree, cortical bone density. One third of women who have been amenorrheic for at least 6 months due to weight loss, without anorexia nervosa, or stress have a vertebral bone density of 2 SD or more below the mean (31). Three to 66% of female athletes are affected by amenorrhea, depending on the type of exercise, intensity, duration, and the athlete’s nutritional status (32, 33, 34). Although some studies suggest that weight-bearing bones may be less severely affected than other parts of the skeleton in athletes (35, 36, 37), bone density is markedly reduced below age-matched norms even at weight-bearing sites in women who exercise enough to induce amenorrhea (21, 36, 38, 39, 40, 41). Vertebral bone density is significantly lower in these amenorrheic athletes compared with that in their eumenorrheic counterparts (32, 38, 39). Drinkwater et al. compared 14 amenorrheic athletes to 14 eumenorrheic athletes of similar age, weight, percent body fat, height, and age of menarche and found lumbar bone density to be 14% lower in the amenorrheic athletes, whereas distal radial measurements did not differ between the groups. The mean vertebral bone density in the amenorrheic athletes (mean age, 25 yr) was equivalent to that of the average woman of 51.2 yr of age (38). Warren et al. studied 51 classical ballet dancers, ages 13–29 yr, half of whom were amenorrheic. She found that bone density was significantly lower in amenorrheic dancers compared with that in their eumenorrheic counterparts at 2 weight-bearing sites, the spine and metatarsal, even after controlling for age. After controlling for weight, the difference between the groups disappeared in the spine, but not in the metatarsal (41). Moreover, amenorrheic athletes are at increased risk for the development of stress fractures. Warren et al. studied 75 professional ballet dancers, ages 18–36 yr, and reported that the incidence of stress fractures was twice as high among dancers with amenorrhea as in those with regular periods (42). Stress fractures have also been shown to be more common in amenorrheic women runners compared with runners who cycle regularly (36). In contrast to anorexia nervosa, spinal compression fractures have not been reported in young women with hypothalamic amenorrhea due to exercise or stress, emphasizing the importance of nutritional factors in patients with amenorrhea due to weight loss.

The importance of weight as a determining factor of spinal bone density in the study by Warren et al. (41) underscores the significant contribution of body composition and nutritional factors in the pathogenesis of hypothalamic amenorrhea and amenorrheic bone loss, particularly in athletes. This is reflected in the term female athlete triad, which has been used to refer to the disordered eating, amenorrhea, and osteopenia that is commonly observed in female athletes attempting to excel at sports (34, 43, 44). The work by Frisch and McArthur in the 1970s was the first to demonstrate a possible weight threshold necessary for normal menstrual function (45). Later studies demonstrated that bone density correlates with weight (46, 47) and that low body weight is associated with an increased risk of fractures (48) in premenopausal women with normal menstrual function.

Evidence that estrogen deficiency is involved in the pathogenesis of bone loss in hypothalamic amenorrhea includes a positive correlation of bone density with duration of amenorrhea, a negative correlation with estradiol levels, and a disproportionate loss of trabecular bone, as in postmenopausal osteopenia (31, 49, 50). Lack of other ovarian hormones, such as testosterone, may also play a role in the pathophysiology of osteopenia in this population. Women with hypothalamic amenorrhea have lower serum free testosterone levels than those in age-matched controls (24). Moreover, a correlation between spinal bone density and free testosterone levels has been demonstrated in women with hypothalamic amenorrhea (31) as well as in larger studies of eumenorrheic premenopausal women (51, 52), suggesting a possible role for androgens in the maintenance of bone mass in premenopausal women and for androgen deficiency in the pathophysiology of bone loss in hypothalamic amenorrhea.

Hypercortisolism may also contribute to bone loss in this population. Subclinical hypercortisolism is prevalent in women with hypothalamic amenorrhea (18, 53, 54). Depression, which is also characterized by subclinical hypercortisolism, is associated with osteopenia independent of menstrual status (55). Cushing’s disease (56) and administration of supraphysiological doses of glucocorticoids (57, 58, 59) are known to cause severe osteopenia. Hypercortisolism-associated derangements in calcium and vitamin D metabolism, including decreased osteoblastic activity, decreased intestinal absorption of calcium, and increased urinary calcium losses, have been described (60, 61, 62, 63, 64, 65, 66, 67), providing potential mechanisms by which hypercortisolism may contribute to bone loss in hypothalamic amenorrhea.

The timing of the onset of hypothalamic amenorrhea is extremely important in determining its impact on bone density. Estrogen deficiency in puberty is particularly devastating because adolescence is a crucial time for bone formation and for eventual attainment of peak bone density (68, 69, 70). Although genetic factors are important in determining peak bone mass (71, 72, 73), hormonal factors clearly play an important role. Delayed menarche and amenorrhea during adolescence are associated with decreased peak bone mass, reflecting a critical window in time during puberty when adequate gonadal steroids are essential for the attainment of peak bone mass. A strong correlation has been demonstrated between the age of menarche and fracture development in professional dancers, with close to 90% of women who had menarche later than 17 yr of age sustaining fractures (Fig. 2Go) (42). In a later study of 51 classical ballet dancers, aged 13–29 yr, age of menarche was the only variable that correlated with the occurrence of stress fractures (r = 0.28; P < 0.004). Moreover, the age of menarche in dancers with stress fractures was significantly higher than that in dancers without stress fractures (15.2 ± 2.62 vs. 13.8 ± 1.9 yr; P < 0.02) (41).



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Figure 2. Relationship between age at menarche and the percentage of subjects with fractures and stress fractures (n = 75). (Reprinted with permission from New England Journal of Medicine, 314:1351, 1986.)

 
Untreated hypothalamic amenorrhea is associated with progressive bone loss during the first 5 yr of amenorrhea, after which the rate of bone loss may significantly decline, as demonstrated by Biller et al. in a prospective evaluation of 17 women, aged 20–42 yr, with hypothalamic amenorrhea (31). However, Drinkwater et al. documented a 6.2% increase in vertebral bone density in a mean follow-up of 14.4 months after the resumption of menses in 7 athletes, in contrast to 2 athletes who remained amenorrheic and continued to lose bone (74). However, bone density did not return to normal (74), and an extended follow-up of a larger cohort would be necessary to determine whether normal bone density for age is eventually achieved. Estrogen therapy is routinely prescribed for young women with acquired GnRH deficiency because of its theoretic benefits in reducing bone turnover, as has been demonstrated in postmenopausal estrogen deficiency. Definitive prospective studies of the effects of estrogen therapy on bone in women with hypothalamic amenorrhea have not been conducted. However, a small retrospective series of 8 women with exercise-induced amenorrhea treated with estrogen replacement therapy for 24–36 weeks showed an increase in vertebral and femoral neck bone density compared with that in women not receiving hormone replacement (75). In addition, one randomized, prospective study of 24 women with hypothalamic amenorrhea demonstrated an improvement in lumbar spine and total body bone mineral density after 12 months of oral contraceptives compared with those after placebo treatment (76). Medroxyprogesterone (10 mg/day) for 10 days a month for 12 months was shown in one double blind, placebo-controlled study to be associated with an increase in spinal bone density in premenopausal women (77). Bisphosphonate therapy has not been studied in premenopausal women, and neither benefits nor risks specific to this population, including potential deleterious effects on fetal development and long term effects on skeletal mineralization, are known. Further study is needed to determine optimal therapy in this population.


    Anorexia nervosa
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
Anorexia nervosa is associated with acquired GnRH deficiency and LH secretory patterns that resemble those of prepubertal and pubertal children (19). The osteoporosis associated with anorexia nervosa is more severe than that seen in other groups with premenopausal estrogen deficiency, probably reflecting the effects of undernutrition itself on bone formation and/or resorption. Unlike other forms of premenopausal osteoporosis, fractures at a variety of skeletal sites are common, with a 7-fold increase in the risk of developing nonspinal fractures compared with that in age-matched women (78). The majority of women with anorexia nervosa have evidence of bone loss, and 50% of women with anorexia nervosa have bone densities more than 2 SD below age-matched means (79, 80, 81). Biller et al. reported an average bone density in 19 young women with anorexia nervosa comparable to that in an average postmenopausal woman in her seventh or eighth decade (31). Although both cortical and trabecular bones are affected, trabecular bone loss is more severe (82). Vertebral bone density has been reported to be as much as 32% below control values in adult women with anorexia nervosa (79, 80, 83, 84, 85, 86, 87), whereas radial bone density is reduced up to 18% below control values (78, 79, 80, 81, 83, 87).

Evidence that estrogen deficiency is important in the pathophysiology of osteopenia in this population includes the fact that amenorrhea is a nearly universal feature of anorexia nervosa and the observation that bone density correlates with the duration of amenorrhea (79, 80, 88). Undernutrition and insulin-like growth factor I deficiency almost certainly contribute to the increased severity of the osteopenia in this population compared with that in other states of estrogen deficiency (80, 89, 90). The roles of increased cortisol levels, decreased calcium and vitamin D intake, and excessive exercise are less clear (78, 91, 92). Women who develop anorexia nervosa before age 18 yr have significantly lower spinal bone densities than those who develop amenorrhea later, independent of the duration of amenorrhea, consistent with the severe impact of this disorder on bone accretion (79).

Although bone density increases with weight recovery and resumption of menses, significant osteopenia may persist (Fig. 3Go) (78, 93, 94, 95). Vertebral bone density is reduced within 1 yr of diagnosis of anorexia nervosa; therefore, early intervention is critical (80). Postmenopausal replacement doses of estrogens have not been proven to reverse osteopenia in anorexia nervosa. In a randomized controlled prospective study of 48 women with anorexia nervosa, no significant increase in spinal bone density was demonstrated after 1.5 yr of treatment with conjugated equine estrogen (CEE; 0.625 mg) and provera compared with that in the control group. In a subset of estrogen- and progestin-treated women less than 70% of ideal body weight, there was a mean 4.0% increase in bone density compared with that in controls of similar low weight who showed a 20.1% decrease in bone density. These data suggest that the response to estrogen replacement therapy may differ according to weight and disease severity, although the study was not designed to address this question specifically (94). Surrogate markers of bone formation have been shown to be decreased in this population (90), consistent with the hypothesis that severe undernutrition may have a selective marked deleterious effect on osteoblast function. Therefore, therapeutic strategies to increase bone formation may have a particular rationale in this population.



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Figure 3. A, Initial and final individual trabecular bone density measurements in six women with anorexia nervosa who had spontaneous resumption of menses. There was a significant (P = 0.01) increase in bone density. B, Initial and final individual trabecular bone density measurements in women with anorexia nervosa who remained amenorrheic. These was a significant (P < 0.0001) difference between the initial and final bone density measurements. The shaded area represents the normal mean bone density ± 1 SD. (Reprinted with permission from Journal of Clinical Endocrinology and Metabolism, 80:902, 1995.)

 

    Iatrogenic gonadotropin deficiency
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
The increasing use of medications that induce hypoestrogenemia through acquired gonadotropin deficiency have also been implicated as causes of osteopenia in young women. GnRH agonist therapy, used to treat severe endometriosis and uterine myomas, has been shown to be associated with a decline in spinal bone density after 6 months of therapy (96, 97, 98, 99, 100). The loss of trabecular bone density appears to be nearly or totally reversible if treatment is limited to a 6-month course (97, 100, 101). Moreover, use of add-back norethindrone (10 mg/day), norethindrone (2.5 mg/day) plus cyclical sodium etidronate, norethisterone (1.2 mg/day), or postmenopausal doses of estrogen plus medroxyprogesterone may reduce or arrest bone loss, although hormonal add-back regimens may reduce the effectiveness of GnRH agonist therapy (96, 98, 99, 102, 103). Progestin therapy, however, is associated with a decrease in high density lipoprotein levels and an increase in low density lipoprotein levels (96, 103). Finkelstein et al. showed that intermittent PTH administration, an experimental therapy, increases bone density in the spine 2.1 ± 1.1% (±SEM) and prevents bone loss in the hip when used for 1 yr (104).

Despite the possible osteotropic effects of progestins (77, 105, 106), long term use of depot medroxyprogesterone acetate may also lead to a decline in bone density (107, 108, 109, 110), presumably by inducing a state of estrogen deficiency. However, the possibility of other risk factors for osteopenia in patients using depot medroxyprogesterone acetate has not been excluded. In the largest study addressing the issue of depot medroxyprogesterone acetate-induced bone loss, Cundy et al. compared spinal bone densities of 200 women who had been using depot medroxyprogesterone acetate for 2–26 yr with those in 350 premenopausal healthy controls and found that bone density was significantly lower in the depot medroxyprogesterone acetate users. In addition, women who had used depot medroxyprogesterone acetate for more than 15 yr had lower z-scores than women who had used it for a shorter time, implying that increased duration of use may result in more severe bone loss. Moreover, women who starting depot medroxyprogesterone acetate before the age of 21 yr had lower z-scores than their counterparts who started later, possibly reflecting a negative impact on attainment of peak bone mass (107). Although bone density increases after discontinuation of depot medroxyprogesterone acetate, recovery may not be complete. In a prospective study, the spinal bone densities of 14 women were measured before and after discontinuation of depot medroxyprogesterone acetate. Twelve months after discontinuation of the contraceptive, there was a mean 3.0% increase in spinal bone density, and after 24 months, bone density had increased a mean of 6.4%. Nevertheless, even 24 months after cessation of depot medroxyprogesterone acetate use, bone density remained 9.0% lower than that in a group of 18 age-matched controls who had never taken the medication (110).


    Ovarian failure
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
Premenopausal bone loss associated with hypogonadism was first recognized in women with a history of surgical oophorectomy (111). In a study investigating the long term effects of oophorectomy in young women, the identified decrease in bone density was accompanied by an increase in fracture risk (112). It was later appreciated that the premature onset of menopause from other causes, including autoimmune or idiopathic (21, 49) and chemotherapy (113, 114, 115), results in a decline in bone density. Bone loss from premature ovarian failure is becoming a more important public health problem as an increasing number of women in the premenopausal age group undergo chemotherapy for treatment of malignancies. Some chemotherapeutic regimens result in a greater than 50% incidence of amenorrhea, primarily attributed to ovarian failure, although hypothalamic amenorrhea has also been reported (116, 117, 118). Although all bone compartments may be affected in women with premature ovarian failure, trabecular bone is more severely reduced than cortical bone, and this preferential bone loss has been identified in other states of amenorrheic premenopausal bone loss (111). Cann et al. demonstrated that women with premature ovarian failure have an average vertebral bone density 21% below that of age-matched eumenorrheic women (21). Obesity, however, may confer some protection against bone loss. Although Bagur et al. confirmed significant spinal and hip bone loss in 28 women with premature menopause from a number of causes, including oophorectomy and idiopathic cessation of menses, he also reported normal bone density for age in a small group of obese women with a body mass index greater than 30 kg/m2 (119). It is not clear what degree of obesity may be necessary for maintenance of bone mass in the absence of normal menstrual function, and this finding needs to be confirmed in a larger population. Nevertheless, the fact that obesity may protect against the bone loss associated with premature menopause raises the interesting question of whether this effect derives from an increased conversion of androgens to estrogens and/or from the mechanical effects of the weight itself.

Although no large prospective randomized trials have been conducted, a variety of small studies suggest that estrogen replacement therapy, in doses shown to be of therapeutic benefit to older postmenopausal women, may increase or prevent a decline in bone density in women with oophorectomy and chemotherapy-induced premature ovarian failure (120, 121, 122, 123, 124, 125, 126). In the largest prospective study, Prior et al. randomized 41 oophorectomized women to receive CEE at a dose of 0.6 mg/day or medroxyprogesterone at a dose of 10 mg/day. CEE prevented bone loss at the spine and hip, whereas those women receiving medroxyprogesterone lost bone at all sites (Fig. 4Go) (126). In women with premature ovarian failure, CEE (0.625 mg/day) plus medroxyprogesterone (5 mg for 10 days each month) prevented bone loss at the distal forearm compared with that in a self-selected group of women who did not receive hormone replacement therapy (120). A retrospective analysis reported that lumbar bone density was higher in 12 oophorectomized women than that in 18 women who had not taken estrogen (123). Two other small uncontrolled studies also reported an increase in spinal bone density with estrogen therapy in women with premature menopause secondary to oophorectomy or chemotherapy (121, 124). In the largest prospective observational study, Byrd et al. followed 1,016 women, aged 22–78 yr, who had undergone oophorectomies and had been receiving estrogen therapy for at least 3 yr for a total of 14,318 patient-yr. The majority of these women were taking 1.25 mg/day CEE. The researchers reported a lower incidence of forearm fractures than expected as determined by previously published data using age-matched women (122). For women with chemotherapy-induced ovarian failure and estrogen-responsive tumors, estrogen therapy is typically contraindicated. Selective estrogen agonist-antagonists and bisphosphonates have been shown to be of therapeutic benefit in postmenopausal women with estrogen deficiency-associated bone loss (127, 128, 129, 130) and may have a role in this population, but to date they have not been tested in premenopausal women.



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Figure 4. Six- and 12-month percent change (±SD) in bone density after premenopausal ovariectomy, determined by dual energy x-ray absorptiometry in the femoral neck by randomized blinded therapy with CEE (0.6 mg/day) or medroxyprogesterone acetate (MPA; 10 mg/day). Annual bone loss was not significant during CEE treatment, but was significant at all sites during MPA therapy. At 12 months, bone density was different between CEE- and MPA-treated women (P = 0.02). (Reprinted with permission from Journal of Bone and Mineral Research, 12:1856 1997.)

 

    Other causes of osteopenia in premenopausal women
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
This review focuses on osteopenia associated with estrogen deficiency due to secondary amenorrhea. However, other etiologies should be contemplated when considering the differential diagnosis of premenopausal osteopenia in amenorrheic women. These fall broadly into two categories: medication use and systemic illness. A common cause of osteopenia in this population is glucocorticoid administration. The incidence of atraumatic fractures in patients receiving long term glucocorticoid therapy is 30–50% (57, 58, 59). Moreover, regular use of inhaled steroids for asthma can result in a dose-related reduction in bone density (131). Glucocorticoids decrease osteoblast activity and intestinal calcium absorption and may have effects on calcium regulatory hormones (58, 61). Animal studies suggest that secondary hypogonadism may also contribute to the osteopenia seen in glucocorticoid-treated patients (132). Although every other day steroid regimens may help preserve the hypothalamic-pituitary-adrenal axis, they do not appear to protect the skeleton (133). Cyclosporine A causes increased bone turnover and severe osteopenia in rats (134, 135). When added to glucocorticoid regimens in transplant patients, the risk of osteopenia rises sharply, with one report of a 44% fracture rate in less than 3 yr (136).

Other medications have also been implicated as causes of bone loss. Anticonvulsants reduce bone density through their effects on vitamin D metabolism (137, 138) as well as by directly affecting bone turnover (139, 140, 141). Heparin administration is associated with a reduction in bone density in premenopausal women, including pregnant women, and no correlation with dose or duration of therapy has been demonstrated (142, 143, 144, 145). Ethanol abuse has been shown to decrease bone formation markers, but not bone density, in premenopausal women. (146). Hyperthyroidism is known to be associated with osteopenia. Although suppressive doses of levothyroxine appear to decrease bone density in postmenopausal women not taking estrogen, prolonged levothyroxine therapy does not appear to be associated with bone loss in eumenorrheic premenopausal women (147).

Cushing’s syndrome, like glucocorticoid administration, results in bone loss. The resultant osteopenia may be completely reversible with cure of the syndrome (148, 149). Hyperparathyroidism is also associated with bone loss. However, in contrast to osteopenia associated with estrogen deficiency, cortical bone mass is preferentially lost (150). Therefore, radial bone density determinations are of more use in hyperparathyroidism than spine or hip density measurements. Treatment of the underlying condition results in an 8–12% increase in bone mass in the first 2–4 yr after surgery (151). Both childhood- and adult-onset GH deficiencies are associated with a reduction in bone density (152, 153, 154). GH treatment of patients with adult-onset GH deficiency increases bone density (155, 156). However, there are few data available regarding gender-specific effects of acquired GH deficiency in young women and the relationship between GH deficiency and gonadal steroids in this group.


    Conclusions
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 
The association of estrogen deficiency and bone loss in young women is well established. Hypogonadism can be a result of premature ovarian failure or acquired GnRH deficiency and results in a reduction in bone density, with preferential trabecular bone loss. Estrogen deficiency during puberty can impair the attainment of normal peak bone density, thereby making women vulnerable to skeletal fractures earlier in life due to abnormalities in bone accretion as well as bone loss. In a eumenorrheic premenopausal woman with osteopenia, a number of systemic diseases and medication use must be considered as possible etiologies of the osteopenia. Because osteopenia in premenopausal women is associated with considerable morbidity due to increased fracture risk, both short term and later in life as the osteopenia progresses, clinical awareness and further research in this area are clearly needed. In addition, abnormal bone accretion in amenorrheic adolescents makes evaluation particularly important in this age group. A better understanding of the pathogenesis of bone loss in young amenorrheic women will be critical in the development of early effective therapeutic strategies to prevent permanent osteopenia.


    Acknowledgments
 
The authors thank Dr. Joel Finkelstein for his helpful comments.


    Footnotes
 
1 This work was supported in part by NIH Grants M01-RR-01066 and R01-DK-52625. Back

Received November 20, 1998.

Revised February 4, 1999.

Accepted February 9, 1999.


    References
 Top
 Introduction
 Acquired GnRH deficiency
 Hyperprolactinemia
 Hypothalamic amenorrhea
 Anorexia nervosa
 Iatrogenic gonadotropin...
 Ovarian failure
 Other causes of osteopenia...
 Conclusions
 References
 

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