The Influence of Depression, Body Mass Index, and Smoking on ...

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The Journal of Clinical Endocrinology & Metabolism 91(4):1496 –1500 Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2005-2515

The Influence of Depression, Body Mass Index, and Smoking on Serum Inhibin B Levels in Late Reproductive-Aged Women G. M. Lambert-Messerlian and B. L. Harlow Department of Pathology and Laboratory Medicine (G.M.L.-M.), Women and Infants Hospital and Brown Medical School, Providence, Rhode Island 02903; and The Obstetrics and Gynecology Epidemiology Center (B.L.H.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 Context: Women experiencing depression have difficult psychosocial functioning, and recent data suggest an earlier onset of menopause. Understanding the biological mechanism for the impairment of reproductive function associated with depression is important.

at study enrollment and two or more other samples over the first 18-month period of follow-up were included.

Objective: The objective of the study was to determine whether a lifetime history of depression is associated with reduced ovarian reserve as reflected in serum levels of the granulosa cell product, inhibin B.

Main Outcome Measure: Serum inhibin B levels were measured.

Design: Residual serum samples from a subset of patients in the Harvard Study of Cycles and Moods were collected. Setting: Patients were recruited from seven Boston-area communities. Patients: Women with or without a history of major depression, based on structured clinical interviews for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, were enrolled. A subset of patients who had provided an early follicular phase blood specimen

S

Intervention: There were no interventions.

Results: Serum FSH levels were higher in women with a history of depression, whereas inhibin B levels did not differ between groups. Body mass index and age were significantly and inversely related to serum inhibin B levels. Smoking history was noted, for the first time, to have a significant negative association with inhibin B levels. Conclusions: Smoking has a direct negative effect on ovarian reserve, as suggested by decreased serum inhibin B levels. In contrast, effects of depression on the reproductive axis may occur at the level of the pituitary and/or hypothalamus rather than at the gonadal level, as suggested by increased serum FSH levels. (J Clin Endocrinol Metab 91: 1496 –1500, 2006)

ERUM LEVELS OF inhibin B in women are derived from the granulosa cell and directly reflect ovarian reserve during the follicular phase of the menstrual cycle. For example, early follicular phase levels of inhibin B are lower in older vs. younger women (1). In fact, a decrease in serum inhibin B levels is one of the earliest indicators of the loss of ovarian reserve associated with the onset of the menopause (2, 3). Levels of inhibin B increase during the course of the follicular phase of the normal menstrual cycle (4), coincident with proliferation of granulosa cells and increased antral follicle numbers (5). Inhibin B levels, either at baseline (6, 7) or during gonadotropin treatment (8, 9), are indicative of follicle number and development and are predictive of the number of oocytes retrieved after ovarian stimulation for in vitro fertilization. Given that the specific inhibin B immunoassay has been available for a relatively short time, there is much to be learned about inhibin B physiology in women and covariates of ovarian inhibin B production and secretion. For example, in addition to age, it was recently reported that body mass

index (BMI) had a profound effect on serum inhibin B levels, with a greater BMI associated with lower levels of inhibin B (10). One study suggests that race may have an effect on inhibin B levels as well (11). In a recent study, Harlow et al. (12) found that a lifetime history of major depression was associated with an early decline in ovarian function, as indicated by an earlier perimenopausal transition. Women with a history of depression demonstrated increased serum FSH and LH hormone, and decreased estradiol, levels relative to nondepressed control women. Given the documented role for ovarian inhibin B in the follicular phase regulation of serum FSH levels (13), we sought to determine whether women with a lifetime history of depression had evidence of an earlier decline in inhibin B levels vs. nondepressed, age-matched controls. Known and potential covariates of inhibin B, such as age, BMI, smoking, parity, and race, were documented and considered in the analysis.

First Published Online January 31, 2006 Abbreviations: BMI, Body mass index; HSMC, Harvard Study of Moods and Cycles. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Study subjects

Subjects and Methods Serum samples for this analysis were obtained from participants in the Harvard Study of Moods and Cycles (HSMC). These subjects were selected from a population-based cross-sectional sample of approximately 6000 women between the ages of 36 and 44 yr residing in seven Boston metropolitan area communities. After achieving a 73% response

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Lambert-Messerlian and Harlow • Inhibin B and Depression

rate to a self-administered questionnaire that assessed menopausal status and past and current depressive symptoms, 4161 women comprised the target population used to identify a sample with and without a lifetime history of major depression. Patients were required to have menstrual cycles at least every 60 d to qualify for enrollment. Further details pertaining to the characteristics of this framed target population can be found elsewhere (14). We enrolled into the HSMC 332 women who met Diagnostic and Statistical Manual of Mental Disorders criteria for major depression and 644 women with no current or past history of major depression based on structured clinical interviews for Diagnostic and Statistical Manual of Mental Disorders, fourth edition (15). These women were representative of the target population with respect to demographic and reproductive characteristics (16). Participants in the HSMC were asked to provide an early follicular phase (d 2– 4 of the menstrual cycle) blood specimen at study enrollment and then every 6 months over a 36-month period of follow-up. Details pertaining to the blood collection procedures can be found elsewhere (12). For this analysis, we selected all subjects that had remained active in the cohort over the first 18 months of the follow-up period and who had provided menstruation-timed early follicular phase blood specimens at study enrollment and during two or more other time periods over the first 18-month period of follow-up. After these exclusions, 149 patients with a lifetime history of depression and 255 women with no depression history were available for analysis of serum inhibin B levels. This study was approved by the Human Subjects Research Committees at the Brigham and Women’s and Women and Infants Hospitals. All participants in this study provided written informed consent.

Immunoassay Inhibin B levels were measured in patient serum samples using an ELISA (Diagnostic Systems Laboratories, Webster, TX), as described previously (4), but with modification of the pretreatment process. In the original method, samples were pretreated by boiling in sodium dodecyl sulfate and adding hydrogen peroxide (4). In the revised method, sample treatment is achieved, at room temperature, during sample incubation. This method has been validated for measurement of inhibin B in human serum (17) and shown to have high correlation with the prior method (r ⫽ 0.91, Diagnostic Systems Laboratories package insert DSL-1084100). All samples were tested, in duplicate, without operator knowledge of group identity. The assay limit of sensitivity was 30 pg/ml, and the inter- and intraassay coefficients of variation were less than 15%. FSH assessments were done as part of an earlier analysis using CoatA-Count immunoradiometric assays. The World Health Organization Second International Reference Preparation (78/549) of human pituitary FSH was used as the standard for FSH.

Data analysis A single mean FSH and inhibin B level was calculated for each patient using all available data (three to four measurements per patient; one at baseline and at least two at 6, 12, or 18 months after baseline). The mean serum FSH or inhibin B levels were categorized and stratified into clinically meaningful groups (poor, average, and good ovarian reserve). FSH levels less than 5.0 mIU/ml were attributed to good ovarian reserve and more than 10.0 mIU/ml with poor ovarian reserve (18). Similarly, inhibin B levels greater than 80 and less than 40 pg/ml were associated with good and poor ovarian reserve, respectively, based on prior publications (7). Mean categorical data were used as a robust measure of each patient’s reproductive status because this method smooths intercycle and interassay variations and thus avoids overinterpretation of any single data point. All analyses were conducted using SAS statistical software (19). We compared the distribution of background and reproductive history characteristics between women with and without adequate levels of ovarian reserve based on the clinically meaningful categories described above. Crude and adjusted odds ratios with 95% confidence intervals were used as the measure of association between good ovarian reserve (⬎80 inhibin B, ⬍5 FSH) and lifetime history of depression, categories of BMI based on the World Health Organization classification of obesity (⬍25, 25–30, ⬎30), and smoking history (never, past, or current).

J Clin Endocrinol Metab, April 2006, 91(4):1496 –1500

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Results

Serum samples were analyzed for inhibin B levels in 404 women. Table 1 illustrates the overall association between categories of inhibin B and FSH and demographic, reproductive, and lifestyle characteristics. There were only 18 nonCaucasian women in the sample set, which precluded any assessments by race. As expected, low inhibin B and high FSH levels were associated with increasing age (P ⬍ 0.05, Table 1). For example, 34% of 44- to 45-yr-old women, but only 20.5% of 36- to 37-yr-old women, had a mean inhibin B level of less than 40 pg/ml. Similarly, 24.4% of 44- to 45-yrold women, but only 2.6% of 36- to 37-yr-old women, had a mean FSH level above 10 mIU/ml. There was a trend for inhibin B levels to decrease and FSH levels to increase with a younger age at menarche, but these differences did not reach statistical significance. There was no consistent trend of hormonal changes with parity. Relative to never smokers, current smokers were more likely to have lower inhibin B levels and less likely to have lower FSH values. Women with a BMI above 30 were more likely to have an inhibin B level less than 40 pg/ml than were women with a BMI less than 25 (43.2 vs. 20.6%, P ⬍ 0.05). However, FSH levels were not significantly affected by BMI. Mean inhibin B levels did not differ significantly by lifetime history of depression, although depressed women were more likely to have higher FSH levels. We used our categories of good ovarian reserve (inhibin B levels ⬎ 80 and FSH values ⬍ 5.0) as the reference by which to assess whether smoking, BMI, or depression was associated with an increased risk of poor ovarian reserve. Inhibin B values did not significantly differ between women with and without a history of depression (regardless of severity) after multivariate adjustment, whereas depression was significantly associated with higher FSH levels as previously reported (Table 2). On the other hand, poor ovarian reserve, as measured by low inhibin B levels, was significantly associated with smoking (odds ratio current smoker ⫽ 2.9; 95% confidence interval 1.1–7.6), but the same association based on FSH values was less apparent. When BMI was assessed independently, there was no consistent trend with poor ovarian reserve measured either through inhibin B or FSH. We assessed the joint effect between smoking and BMI on inhibin B levels (Table 2). Compared with women with inhibin B levels indicative of those with good ovarian reserve (⬎80), those with somewhat reduced ovarian reserve (40 – 80) were twice as likely to be either smokers or women with heavier BMI (⬎25) and nearly five times more likely to be both smokers and women with greater BMI. Relative to these same women with good ovarian reserve, those with the greatest reduction in ovarian reserve (⬍40) were nearly five times as likely to be either smokers or women with heavier BMI but more than 12 times more likely to be both smokers and women with greater BMI. Although smoking and increased BMI increased the odds for reduced inhibin B levels, these variables did not have the same negative effect on serum FSH levels. There was no difference in the likelihood of having a good (⬍5) or moderate (5–10 mIU/ml) FSH level based on smoking or BMI. Paradoxically, the odds of having a poor FSH level (⬎10 mIU/ml) were reduced by a history

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TABLE 1. Differences in mean inhibin B and FSH over 18 months of follow-up by characteristics of the population n

All women Age (yr)b 36 –37 38 –39 40 – 41 42– 43 44 – 45 Age at menarche (yr) ⱕ10 11 12–13 14 ⱖ15 Parity 0 1 2 ⱖ3 Smoking Never smoked Past smoker Current smoker BMI (kg/m2)c ⬍25 25–30 ⬎30 Depressiond No history Less severe history More severe history

Categories of mean inhibin B (%)

Categories of mean FSH (%)

⬎80

40 – 80

⬍40a

⬍5.0

5.0 –10.0

⬎10.0

404

33.7

39.4

26.9

27.0

57.2

15.8

78 112 93 80 41

38.5 45.5 30.1 21.3 24.4

41.0 34.8 39.8 42.5 41.5

20.5 19.6 30.1 36.3 34.1

46.2 32.1 19.4 15.0 17.1

51.3 59.8 57.0 58.8 58.5

2.6 8.0 23.7 26.3 24.4

19 48 253 47 37

10.5 41.7 32.8 29.8 46.0

42.1 31.3 41.1 40.4 35.1

47.4 27.1 26.1 29.8 18.9

31.6 27.1 27.7 21.3 27.0

36.8 52.1 57.3 66.0 62.2

31.6 20.8 15.0 12.8 10.8

183 59 96 66

37.2 27.1 29.2 36.4

39.3 37.3 38.5 42.4

23.5 35.6 32.3 21.2

27.3 20.3 25.0 34.9

60.1 54.2 55.2 54.6

12.6 25.4 19.8 10.6

201 146 57

39.8 27.4 28.1

36.8 43.2 38.6

23.3 29.5 33.3

29.4 27.4 17.5

53.2 58.2 68.4

17.4 14.4 14.0

262 91 51

40.8 20.9 19.6

38.6 42.9 37.3

20.6 36.3 43.2

23.7 29.7 39.2

58.4 58.2 49.0

17.9 12.1 11.8

255 84 65

31.4 38.8 36.9

41.2 32.5 41.5

27.5 28.8 21.5

28.2 23.8 27.7

58.8 58.8 50.8

12.9 17.5 21.5

a

Includes 64 women with nondetectable inhibins in all samples. P ⬍ 0.05 for inhibin B and FSH. c P ⬍ 0.05 for inhibin B only. d Less severe history defined as a lifetime duration of episodes 24 months or less, and total number of episodes are three or less. More severe history defined as lifetime duration of episodes longer than 24 months or total number of episodes greater than three. b

of smoking and/or a BMI greater than 25. Lastly, as expected, increased serum FSH levels were associated with decreased serum inhibin B levels, and vice versa, after adjustment for confounding variables. Discussion

Although women with a history of depression showed an earlier perimenopausal transition, as evidenced by earlier menstrual irregularities and an altered endocrine status, such as increased serum FSH levels (12), inhibin B levels were similar in women with and without depression history with roughly about 30% of each group having high (⬎80 pg/ml), medium, and low (⬍40 pg/ml) levels. Therefore, depression seems not to have direct effects on ovarian reserve. Rather, the effects of depression on the reproductive axis may be mediated in the central nervous system with primary effects at the level of the pituitary (and/or hypothalamus) resulting in increased serum FSH levels. A dose effect was apparent, with serum FSH levels significantly increased in women with severe depression but only slightly increased in women with mild depression. One may speculate that decreased inhibin B may become evident in depressed women at time points beyond 18 months by ovarian depletion after more prolonged exposure to increased serum FSH levels. A novel and unexpected finding of the present study was

the profound effect of cigarette smoking on inhibin B levels. Smoking has long been known to compromise fertility and lead to an earlier onset of menopause (20). The mechanism by which smoking diminishes reproductive capacity in women is unknown. There are nicotine receptors in the central nervous system and effects on the hypothalamic-pituitary axis are suggested by increased serum FSH (21), but not LH (22), levels in women who smoke. FSH was not significantly affected by smoking in the present study. On the other hand, there is also evidence for a direct effect of smoking on ovarian follicles, not the least of which is the present finding of significantly reduced levels of inhibin B. Smoking was associated with reduced follicle counts in normal (removed primarily for fibroids) ovaries (23) and poor response in clomiphene citrate challenge tests (24). Nicotine has been shown to directly impair granulosa cell aromatase activity and progesterone synthesis, and smoking was associated with reduced luteal progesterone metabolites (25). Taken together, these data support a direct toxic effect of cigarette smoke on ovarian follicle number and function. However, one recent study (26) found no association of current smoking and inhibin B levels. There may be differences between the studies with regard to the amount and duration of smoking that may explain the discrepant result. The smokers in the current study smoked an average of 17 cigarettes per day and



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TABLE 2. Influence of depression, smoking, and BMI on mean inhibin levels based on four samples over an 18-month period Mean inhibin-B ⬎80

Mean FSH ⬍40

40 – 80

%

%

ORa (95%CI)

%

No Hx of depression Less severe historyb More severe depressionb

31.4 38.8 36.9

41.2 32.5 41.5

1.0 0.5 (0.2–1.0) 0.6 (0.3–1.2)

27.4 28.8 21.5

Never smoked Past smoker Current smoker

39.8 27.4 28.1

36.8 43.2 38.6

1.0 1.7 (1.0 –3.0) 1.4 (0.6 –3.2)

BMI ⬍25 25–30 ⬎30

40.8 20.9 19.6

38.6 42.9 37.3

Never smoked/BMI ⬍25 Ever smoked/BMI ⬍25 Never smoked/BMI ⬎25 Ever smoked/BMI ⬎25

46.1 31.5 31.5 17.1

Mean FSH ⬍5 5–10 ⬎10

42.1 37.7 4.7

ORa (95%CI)

⬍5.0

⬎10.0

5.0 –10.0

%

%

ORa (95%CI)

%

1.0 0.6 (0.3–1.4) 0.5 (0.2–1.3)

28.2 23.8 27.7

58.8 58.8 50.8

1.0 1.0 (0.5–1.9) 0.7 (0.3–1.4)

12.9 17.5 21.5

1.0 2.1 (0.6 – 6.8) 5.1 (1.3–19.4)

23.3 29.5 33.2

1.0 2.1 (1.0 – 4.3) 2.9 (1.1–7.6)

29.4 27.4 17.5

53.2 58.2 68.4

1.0 1.2 (0.7–2.0) 2.3 (1.0 –5.2)

17.4 14.4 14.0

1.0 0.5 (0.2–1.4) 2.6 (0.7–10.4)

1.0 4.0 (0.9 –17.9) 0.8 (0.3–2.1)

20.6 36.3 43.2

1.0 3.9 (0.7–20.7) 1.3 (0.4 – 4.1)

23.7 29.7 39.2

58.4 58.2 49.0

1.0 1.2 (0.4 – 4.2) 0.6 (0.2–1.3)

17.9 12.1 11.8

1.0 0.3 (0.03–3.2) 0.6 (0.1–2.6)

38.3 37.0 37.0 46.3

1.0 1.8 (1.0 –3.2) 1.8 (1.0 –3.2) 4.6 (2.1–9.9)

15.6 31.5 31.5 36.6

1.0 4.5 (2.0 –10.0) 4.5 (2.0 –10.0) 12.6 (4.6 –34.6)

24.8 28.2 28.2 28.1

54.6 58.6 58.6 58.5

1.0 0.9 (0.5–1.6) 0.9 (0.5–1.6) 0.9 (0.5–1.8)

20.6 13.3 13.3 13.4

1.0 0.4 (0.1–1.0) 0.4 (0.1–1.0) 0.2 (0.1– 0.6)

42.2 38.1 39.1

1.0 1.0 (0.6 –1.8) 13.5 (3.5–53.1)

15.6 24.2 56.3

1.0 1.8 (0.8 –3.8) 43.0 (10.0 –184.1) 38.8 28.9 15.6

64.0 55.4 51.4

1.0 1.1 (0.6 –1.8) 1.8 (0.9 –3.8)

2.2 15.7 33.0

Mean inhibin ⬍80 40 – 80 ⬎40

ORa (95%CI)

1.0 13.1 (2.8 – 61.1) 72.2 (13.3– 413.8)

a

Odds ratio (OR) adjusted for age, menarche, parity, and each variable in the table simultaneously. Less severe history (Hx) defined as a lifetime duration of episodes ⱕ24 months, and total number of episodes are three or less. More severe history defined as lifetime duration of episodes ⬎24 months, or total number of episodes greater than three. b

had been smoking for 17 yr, but the level of smoking in the conflicting study (26) was not reported. At minimum, future studies of inhibin B levels in women must consider smoking as a confounding variable. The present results corroborate previous findings of decreased ovarian inhibin B levels in women with advancing age (2, 3) or increased BMI (10, 26, 27). The mechanism by which an increased BMI may decrease inhibin B could result from a simple dilution effect by a higher blood volume or a more complex hypothalamic regulation. The trend for decreased FSH levels in patients with relatively high BMIs may be suggestive of a potential hypothalamic mechanism. On the other hand, the present study also failed to demonstrate a significant effect of BMI on serum FSH levels. Welt et al. (28) discounted a causal relationship between LH and inhibin B; acute human chorionic gonadotropin administration increased, rather than decreased, serum inhibin B levels. They proposed that increased serum insulin levels, associated with increased BMI, could suppress inhibin B levels by inhibiting follicle growth and granulosa cell proliferation. Regardless of the mechanism, reproductive status has a profound influence on the interaction of BMI and inhibin B levels; whereas increased BMI suppresses inhibin B levels in premenopausal women, the relationship is reversed after the menopause (26). The effects of BMI and smoking on inhibin B levels were additive. Inhibin B levels were four times as likely to be low in women who either had an increased BMI or smoked but were 12 times as likely to be low in women who had an increased BMI and smoked. FSH levels were not significantly altered in either women with increased BMI or smokers;

however, women with both characteristics demonstrated reduced FSH levels. This reduction in FSH is likely explained by the profound loss of inhibin B in smoking women with increased BMI and a loss of negative feedback to pituitary FSH. Overall, the interaction of these effects again suggests that BMI and smoking act directly on the ovary to diminish reserve and serum inhibin B levels. A history of depression has been shown to impair the reproductive axis. Increased serum FSH levels and an earlier onset of menopause have been previously reported (12). The mechanism of action for this process is not understood. The present results suggest that the effect is mediated through the central nervous system in that: 1) there was a dose-response effect on serum FSH levels, with more severe cases of depression having more profoundly increased levels, and 2) effects on the ovary, namely decreased inhibin B levels, were not simultaneously appreciated. We speculate that inhibin B changes would be apparent, given a longer patient follow-up duration (i.e. longer than 18 months). In contrast, smoking and an increased BMI were associated with decreased inhibin B levels, suggesting a direct detrimental effect on the ovary. Future studies to establish a causal relationship between smoking and diminished ovarian reserve and explain the mechanism(s) of action for this effect are important. Acknowledgments Received November 18, 2005. Accepted January 24, 2006. Address all correspondence and requests for reprints to: Geralyn Lambert-Messerlian, Ph.D., Prenatal and Special Testing, Women and Infants Hospital, 70 Elm Street, Suite 2, Providence, Rhode Island 02903. E-mail: [email protected].

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This work was supported in part by sponsored research funding from Diagnostic Systems Laboratories, Inc. (to G.M.L.-M.) and the National Institutes for Health Grant MH-50013 (to B.L.H.). Current address for B.L.H.: Division of Epidemiology and Community Health, University of Minnesota, 1300 South Second Street, Suite 300, Minneapolis, Minnesota 55454. G.M.L.-M. is a consultant for Diagnostic Systems Laboratories, Inc. (Webster, TX).

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.