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Psychosomatic Medicine 63:361-364 (2001)
© 2001 American Psychosomatic Society

ORIGINAL ARTICLES

Are Women With Premenstrual Dysphoric Disorder Prone to Osteoporosis?

Uriel Halbreich, MD and Linda S. Kahn, PhD

From the BioBehavioral Program, School of Medicine and Biomedical Sciences, State University of New York at Buffalo.

Address reprint requests to: Uriel Halbreich, MD, BioBehavioral Program, School of Medicine and Biomedical Sciences, SUNY Clinical Center, Room BB170, 462 Grider St., Buffalo, NY 14215. Email: urielh{at}acsu.buffalo.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: The objective of this study was to examine whether bone mineral density (BMD) is reduced in women with premenstrual dysphoric disorder (PMDD).

METHODS: Thirty-eight healthy women participated: 20 with prospectively confirmed PMDD and 18 without PMDD. Bone mass was measured using dual-energy x-ray absorptiometry at three sites: lumbar spine anteroposterior, lumber spine lateral, and femoral neck. Results from the PMDD and control groups were compared with each other and with age- and sex-matched normative data.

RESULTS: The BMD of both groups was as expected for their age and sex, and groups did not differ in BMD or Z scores for any of the bone sites studied.

CONCLUSIONS: If women with PMDD are at an increased risk of developing osteoporosis, this risk is not manifested in their BMD.

Key Words: premenstrual dysphoric disorder • premenstrual syndrome • osteoporosis • bone metabolism.

Abbreviations: AP = anteroposterior; BMD = bone mineral density; DSM-III-R =Diagnostic and Statistical Manual of Mental Disorders, third edition, revised; DSM-IV =Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DXA = dual-energy x-ray absorptiometry; LLPDD = late luteal phase dysphoric disorder; PMDD = premenstrual dysphoric disorder; PMS = premenstrual syndrome; SCID = Structured Clinical Interview for DSM-III-R.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Decreased BMD in patients with affective disorders has been reported by several groups (1–3). It has been suggested that women who suffer from PMS have lower BMD and are thus at increased risk of developing osteoporosis (4, 5). Given the heightened public awareness of postmenopausal women’s vulnerability to osteoporosis, identification of young women prone to this disorder would enable earlier intervention.

Dysphoric PMS, or PMDD, has been suggested to be associated with affective disorders (6, 7). About half of women with PMDD have a lifetime history of depressions or might be at a higher risk of developing major depressive disorder (7). The etiology of PMS is probably a complex interaction between genetic vulnerability, fluctuating activity of gonadal hormones as well as other biological processes, and the influence of these hormones and processes on neurotransmitters and other brain processes. Among others, abnormalities of the serotonergic and {gamma}-aminobutyric acid systems, similar to those reported in major depressive disorder, have also been found among women with PMS or PMDD (8, 9).

Several recent studies have raised questions about calcium deficiency and reduced BMD among women with PMS (4, 5, 10, 11). Thys-Jacobs et al. (5) reported that 26 women with PMS had significantly lower 25(OH)D levels (19.5 ± 7.5 vs. 25.3 ± 8.3 ng/ml) and higher serum calcium levels (2.4 ± 0.1 vs. 2.3 ± 0.1 mmol/liter), along with reduced BMD at the L2 to L4 site (1.18 ± 0.11 vs. 1.28 ± 0.11 g/cm2, p = .0016) and the Ward’s triangle area (0.84 ± 0.10 vs. 0.91 ± 0.16 g/cm2, p = .0458), as compared with 20 control subjects but no differences at the femoral neck and trochanter. Lee and Kanis (4) reported that a retrospectively reported history of PMS was more prevalent among postmenopausal women diagnosed with osteoporosis. This report would be in accord with those of Thys-Jacobs et al. (10, 11), who reported that calcium carbonate reduced premenstrual mood and physical symptoms by 50%. Nevertheless, retrospective reports of PMS have been consistently shown to be unreliable, especially when they are recalled years after the last actual menses.

It has been suggested that women with PMS might have impaired bioavailability of vitamin D as well as calcium deficiencies. These conditions would contribute to secondary hyperparathyroidism and increased bone resorption and loss (12).

Decreased BMD in patients with affective and other disorders may be due to a multitude of interacting mechanisms (13). These mechanisms include hypercortisolemia, alcohol abuse and cigarette smoking, hyperprolactinemia (often caused by psychotropic medications), decreased estrogen activity, as well as increased levels of central and peripheral interleukins (1, 13). Before embarking on detailed labor- and cost-intensive evaluations of pathobiological processes, we wished to confirm the reports of decreased BMD in women with PMDD.

The study reported here compared the BMD of physically healthy women with prospectively confirmed PMDD with the BMD of those without premenstrual mood or physical symptoms. We anticipated that women with PMDD would show reduced BMD compared with control subjects.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
Thirty-eight women between the ages of 20 and 45 participated in the study: 20 healthy women with PMDD (mean age = 35.9 years, SD = 5.5) and 18 healthy women without PMDD or other premenstrual symptoms (mean age = 34.2 years, SD = 7.8). The age of the two groups did not differ (t = 0.81, p = .43). Written informed consent was obtained from all subjects before participation.

All subjects were physically healthy. Physical examinations did not reveal any findings that would have necessitated medical interventions, and all routine laboratory screening values (eg, liver and kidney function, glucose, enzymes, and electrolytes) were within normal limits. In addition, all subjects had regular menstrual cycles (24–32 days), were not perimenopausal, and did not meet criteria for any DSM-III-R axis 1 diagnosis (14) as determined by the Structured Clinical Interview for DSM-III-R (15) for at least the past 2 years. All subjects were white, and their weight was within ±20% of optimal for their height and frame. All subjects were medication free and used mechanical methods of birth control. Patients were excluded from the study if they were heavy smokers (>20 cigarettes per day, present or past), used medications known to affect calcium metabolism, abused alcohol or illicit drugs, had a history of metabolic bone disease, or had diagnosed endocrinopathy.

Patients were recruited by an advertisement seeking women with PMS. Patients met criteria for LLPDD (14), which was prospectively confirmed by monitoring symptoms with a modified Daily Rating Form (16) for at least 2 cycles. Relevant symptom items for LLPDD and PMDD on the rating form showed severity levels lower than 3 (moderate on a scale of 1 to 6, nonexistent to extremely severe) during the midfollicular phase (days 6–10 of the menstrual cycle) and higher than 4 (marked) during the late luteal phase (days -6 to -1 before the next menses), and a change of at least 2 points and 75% from the midfollicular to the late luteal phase. Post hoc evaluation showed that the women with LLPDD would also meet DSM-IV criteria for PMDD (17).

Healthy control women were recruited by an advertisement seeking volunteers for studies of the menstrual cycle. Control subjects underwent the same evaluation process and completed the same prospective Daily Rating Form, but they did not even marginally meet criteria for LLPDD (no dysphoric symptoms with severity levels >3 reported). Ovulation was determined with luteinizing hormone urine tests. All subjects were studied during ovulatory cycles.

Patients and control women were a consecutive group of women who had been involved in an ongoing PMS and other women’s life-cycle program. Estradiol levels of the two groups were similar. Glucocorticoid levels were not measured in this protocol.

Bone Mass Measurements
BMD was measured using a Hologic QDR-2000 x-ray bone densitometer, which uses multiple detector fan-beam DXA. This machine estimates bone mineral content (in g) and areal BMD (in g/cm2). The manufacturer’s acceptable limits of rate of change are <2% per year (error of estimate of BMD <2%).

BMD was determined in the lumbar spine (L2–L4) and in the right femoral neck, both of which are common sites prone to osteoporosis-related bone fractures and are accessible to DXA. BMD values obtained by DXA have direct clinical applications because the strength of the bone is directly related to its mineral content and mass (18).

Data Analysis
Hologic software integrated in the bone densitometer was used to compare each woman’s BMD with age- and sex-matched norms. Quality-control software is built into the DXA machine. Generated data are presented as actual BMD as well as Z scores (the difference between each patient’s BMD and the mean normative values for their age, expressed as standard deviations). The BMD and Z scores of the two groups were compared with each other using nonpaired Student’s t tests.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Individual BMD values at the lumbar spine lateral site of both groups (compared with age- and sex-matched normative data) are illustrated in Figure 1. This figure demonstrates that all BMD values are within the normal range (±1 SD of mean). It also illustrates the similarity in BMD between women with and women without PMDD. Both groups had BMD values very close to the normative means for their age.



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  		Fig. 1. BMD at the lumbar spine lateral in women with PMDD (N = 20) and women with no PMDD or PMS (N = 18).

 
The mean BMD measurements and Z scores for the lumbar spine AP, lumbar spine lateral, and femoral neck sites are shown in Table 1. For all three locations, there is no significant difference in BMD between women with PMDD and control subjects. The Z scores indicate that the BMD of the PMDD group and the control group fall within the normal range for women in each age category (BMD: lumbar spine AP, t = 0.264, p = .794; lumbar spine lateral, t = 1.56, p = .128; femoral neck, t = 0.388, p = .700; Z scores: lumbar spine AP, t = 0.827, p = .413; lumbar spine lateral, t = 1.56, p = .127; femoral neck, t = 0.081, p = .936).


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  		Table 1. BMD in Women of Reproductive Agea
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
It is demonstrated here that in healthy women with carefully, prospectively diagnosed PMDD there was not even a trend toward reduced BMD. Therefore we cannot substantiate the suggestion that women with PMDD are at greater risk for developing osteoporosis than women in general, nor that this risk may be detected by BMD before menopause. Given the number of women studied here (20 with PMDD and 18 control subjects), a chance of a statistical Type II error might be raised. However, the almost negligible Z scores and the high p values render such a possibility unlikely. Our sample size is similar to that of Thys-Jacobs (26 patients and 20 control subjects), who reported (5) a relationship between BMD and PMS. It is also similar to sample sizes of studies reporting reduced BMD in women with major depressive disorder (3, 13).

Previous reports, although suggesting a relationship between PMS and lower BMD, are inconclusive. Thys-Jacobs et al. (5) reported slight differences in BMD among 26 women with PMS at the L2 to L4 site and at the Ward’s triangle compared with 20 control subjects. No differences in BMD at the femoral neck or trochanter were reported.

Although Lee and Kanis (4) reported a relationship between postmenopausal osteoporosis and a history of PMS, their results were based on retrospective recollections of PMS, which have been shown to be of questionable reliability even in women who were still of reproductive age (6, 19).

Osteoporosis can be viewed as a disorder of impaired homeostatic regulation (20, 21) that involves abnormal regulatory processes and levels of vitamin D and calcium, which are influenced by pituitary and gonadal hormones as well as prolactin, dopamine, a multitude of psychotropic medications and nicotine, dietary deficiencies, sunshine, hyperparathyroidism, metabolic processes, interleukins, and several other functions. The possible association between these processes and decreased BMD in mental disorders was previously reported and reviewed by us (1, 13).

Normal BMD among women of reproductive age with or without PMDD does not necessarily indicate that calcium or any of the multiple processes involved in bone formation and resorption are not involved in the pathophysiology of PMDD and other premenstrual symptoms, contributing to precipitation or exacerbation of symptoms (13). The pathophysiology of PMDD and PMS is multidimensional and probably involves multiple interacting processes (9, 22), as do the biology and pathobiology of bone dynamics. By design, our subjects with PMDD were free of major affective disorders. Thus we cannot address the question of altered bone density in the other patient group. In any case the summation of the bone homeostatic processes in women with PMDD (or dysphoric PMS) seems to be well within normal limits.

Data are presented as means ± standard deviations. All differences between women were not significant (t values, 0.081–1.56; p values, 0.936–0.127)


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
Collection of data was partially supported by Grant RO1-46901 from the National Institute of Mental Health.

Received for publication March 22, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Halbreich U, Rojansky N, Palter S, Hreshchyshyn M, Kreeger J, Bakhai Y, Rosan R. Decreased bone mineral density in medicated psychiatric patients. Psychosom Med 1995; 57: 485–91.[Abstract/Free Full Text]
  2. Schweiger U, Deuschle M, Korner A, Lammers C, Schmider J, Gotthardt U, Holsboer F, Heuser I. Low lumbar bone mineral density in patients with major depression. Am J Psychiatry 1994; 151: 1691–3.[Abstract/Free Full Text]
  3. Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, Chrousos G, Gold P. Bone mineral density in women with depression. N Engl J Med 1996; 335: 1176–81.[Abstract/Free Full Text]
  4. Lee S, Kanis J. An association between osteoporosis and premenstrual symptoms and postmenopausal symptoms. Bone Mineral 1994; 24: 127–34.[Medline]
  5. Thys-Jacobs S, Silverton M, Alvir J, Paddison P, Rico M, Goldsmith S. Reduced bone mass in women with premenstrual syndrome. J Womens Health 1995; 4: 161–8.
  6. Halbreich U, Endicott J. Relationship of dysphoric premenstrual changes to depressive disorders. Acta Psychiatr Scand 1985; 71: 331–8.[Medline]
  7. Yonkers KA. The association between premenstrual dysphoric disorder and other mood disorders. J Clin Psychiatry 1997; 58(Suppl 15): 19–25.
  8. Halbreich U, Petty F, Yonkers K, Kramer GL, Rush AJ, Bibi KW. Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder. Am J Psychiatry 1996; 153: 718–20.[Abstract/Free Full Text]
  9. Halbreich U. Premenstrual syndromes: closing the 20th century chapters. Curr Opin Obstet Gynecol 1999; 11: 265–70.[Medline]
  10. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Am J Obstet Gynecol 1998; 179: 444–52.[Medline]
  11. Thys-Jacobs S, Ceccarelli S. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med 1989; 4: 183–9.[Medline]
  12. Thys-Jacobs S, Alvir M. Calcium-regulating hormones across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS. J Clin Endocrinol Metab 1995; 80: 2227–32.[Abstract]
  13. Halbreich U, Palter S. Accelerated osteoporosis in psychiatric patients: possible pathophysiological processes. Schizophr Bull 1996; 22: 447–54.
  14. DSM-III. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington DC: American Psychiatric Association; 1987.
  15. SCID-P. Structured clinical interview for DSM-III-R–patient edition (SCID-P). Washington DC: American Psychiatric Association; 1990.
  16. Endicott J, Nee J, Cohen J, Halbreich U. Premenstrual changes: patterns and correlates of daily ratings. J Affect Disord 1986; 10: 127–35.[Medline]
  17. DSM-IV. Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Association; 1994.
  18. Cummings S, Kelsey J, Nevitt M, O’Dowd K. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 1985; 7: 178–208.[Free Full Text]
  19. Endicott J, Halbreich U. Retrospective report of premenstrual depressive changes: factors affecting confirmation by daily ratings. Psychopharmacol Bull 1982; 18: 109–12.
  20. Riggs BL. Osteoporosis—a disease of impaired homeostatic regulation. Miner Electrolyte Metab 1981; 5: 265–72.
  21. Steele FR. Evolutions: bone remodeling. J Natl Inst Health Res 1985; 7: 78–87.
  22. Halbreich U. Premenstrual dysphoric disorders: a diversified cluster of vulnerability traits to depression. Acta Psychiatr Scand 1997; 95: 169–76.[Medline]



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