Association between sex steroids, ovarian reserve, and vitamin D levels in healthy non-obese women Eun Mi Chang, M.D, You Shin Kim, M.D, Hyung Jae Won, M.D, Tae Ki Yoon, M.D, Ph.D, Woo Sik Lee,M.D, Ph.D Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, Seoul 135– 081, Republic of Korea

Context: Vitamin D maintains calcium and phosphorous homeostasis and promotes bone mineralization; however, its non-skeletal functions are increasingly being recognized. Recent evidence supports a role for vitamin D in reproductive potential but few studies have investigated the potential effects of vitamin D on reproductive hormone biosynthesis and ovarian reserve. Objective: The aim of this study was to determine the relationships between the serum level of vitamin D, reproductive hormone levels, and ovarian reserve in healthy non-obese women. Design: This was a cross-sectional study. Setting: The study was performed at the Fertility Center at CHA Medical Center. Participants: Seventy-three healthy women volunteers were participated in this study. The participants were non-obese parous women with regular menstrual cycles and no history of infertility. Main Outcome Measures: We determined serum levels of vitamin D, steroid hormones, sex hormone-binding globulin, ovarian reserve markers, homeostatic model assessment-insulin resistance index (HOMAIR), and lipid profiles. Results: In linear regression analysis adjusting for age, body mass index, HOMAIR, and lipid profile, serum vitamin D level positively correlated with total testosterone (P⬍0.001) and free androgen index (P⬍0.001), but did not correlate with dehydroepiandrosterone sulfate or other steroid hormones. Spline regression suggested relationship between 25(OH)D and total testosterone was most pronounced at 25(OH)D concentration above 13 ng/ml (␤ coefficient 2.374, 95% CI 1.435– 3.313). Serum vitamin D level was not associated with levels of ovarian reserve markers. Conclusion: Our study revealed a positive correlation between serum vitamin D level and testosterone level in healthy non-obese women, suggesting that vitamin D may increase fertility through the modulation of androgen activity. The possible causality of the relationship between vitamin D and testosterone deserves further investigation.

itamin D is a steroid hormone precursor that was originally recognized for its importance in calcium– phosphate homeostasis and bone health (1, 2). However, the recent pandemic of vitamin D deficiency has highlighted its nonskeletal functions (3). Mounting evidence suggests that vitamin D deficiency increases the risk of numerous chronic conditions such as type 1 diabetes mellitus; obesity; certain types of cancer; cardiovascular, au-

V

toimmune, and infectious diseases; and psychological disorders including depression and chronic pain (3). Observational studies have also demonstrated that vitamin D deficiency affects both insulin secretion and metabolism, which relates to development of polycystic ovarian syndrome (4). Moreover, maternal vitamin D deficiency have shown to be independently associated with preeclampsia, gestational diabetes mellitus, preterm

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received October 23, 2013. Accepted April 10, 2014.

Abbreviations:

doi: 10.1210/jc.2013-3873

J Clin Endocrinol Metab

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birth, small for gestational age (SGA) infants, and even with fetal programming via specific target organ effects or epigenetic modification (5, 6). More recently, a role for vitamin D in the regulation of fertility has been reported (7). It has long been suggested that the natural conception rate is associated with seasonal differences in light exposure in humans and other animals (8 –10). Studies of assisted technologies have reported that reproductive outcomes vary significantly according to the season, with lower rates of oocyte maturation in the winter months (11–13). Considering the direct relationship between light exposure and vitamin D level, the seasonal variation in fertility can be partially described by vitamin D status. Mice carrying a knockout of vitamin D receptor exhibit hypoplasia, gonadal insufficiency, reduced aromatase gene expression, impaired folliculogenesis, and infertility (14). Similarly, vitamin D deprivation results in gonadal insufficiency in female rats, with overall fertility reduced to 75% that of vitamin D-replete rats (15). Although the correlation between vitamin D and reproductive function has been clearly demonstrated in animals, severe vitamin D deficiency in humans is typically detected in childhood and corrected before the child reaches reproductive age. Thus, little information is available in humans other than a study that reported diminished fertility in individuals with hereditary rickets (16). Recently, vitamin D status has been suggested as a predictor of ovarian response to ovulation induction and low success rate after assisted reproductive technology (17, 18); however, the mechanism underlying the relationship between vitamin D and reproductive outcome is unclear. Gonad function may be altered by vitamin D deficiency, as evidenced by the expression of vitamin D receptor mRNA in human ovaries, mixed ovarian cell cultures, and granulosa cell cultures. In addition, 1,25-dihydroxyvitamin D3 stimulates estrogen and progesterone production through direct regulation of aromatase gene expression in cultured ovarian cells (19). Other studies have suggested that vitamin D status is associated with ovarian reserve (20, 21). To better understand the effect of vitamin D in human reproduction, we carried out a cross sectional study to evaluate interrelationships among hormones of the hypothalamic-pituitary-ovary axis, ovarian reserve, and vitamin D in healthy nonobese women. We hypothesized that vitamin D deficiency alters steroidogenesis and ovarian reserve, which may in turn reduce reproductive capacity.

Materials and Methods Healthy nonobese parous women volunteers of reproductive age with no history of infertility were recruited by public notice at

J Clin Endocrinol Metab

fertility center of CHA Gangnam Medical Center. Eligibility criteria included regular menstrual cycles with no known systemic disease (eg, endocrine or gynecologic disorders) or history of cigarette smoking, and no medication or no nutritional supplements within the previous 3 months. All women were of Korean ethnicity (East Asian) and residents of Seoul, South Korea (37°33⬘58.87“N 126°58⬘40.63”E). All subjects provided written informed consent prior to inclusion in the study, and the study was approved by the CHA University Institutional Review Board for conduct of research on human subjects. We obtained blood specimens in the morning of day 3 of a spontaneous menstrual cycle after overnight fasting. These specimens were stored at –70°C until assayed. To account for seasonal differences in vitamin D levels, all blood specimens were obtained in winter (December or January).

Biochemical assays Serum 25-hydroxyvitamin D [25(OH)D] concentration was determined using a ␥ counter (1470 Wizard, PerkinElmer, Finland) and radioimmunoassay (RIA) kit (DiaSorin, Stillwater, MN, USA) which were validated and standardized according to LC-MS/MS method. Interassay coefficients of variation were 11.7% (at 8.6 ng/ml), 10.5% (22.7 ng/ml), 8.6% (33.0 ng/ml), and 12.5% (49.0ng/ml). Vitamin D deficiency and insufficiency were defined as serum 25(OH)D level ⬍ 10ng/ml and ⬍ 20ng/ml, respectively. Serum levels of sex hormones including basal serum levels of follicle-stimulating hormone (FSH), lutenizing hormone (LH), estradiol (E2), total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS) and 17␣-hydroxyprogesterone were measured using a chemiluminescent immunoassay with UniCel® DxI 800 (Beckman Coulter, Inc., Brea, CA) Beckman Access® Immunoassay System. Serum AMH was analyzed using the the enzymatically amplified two-site AMH-Gen-II ELISA (Beckman–Coulter Inc., Brea, CA). Sex-hormone binding globulin (SHBG) was measured by chemiluminescent immunoassay using Cobas e analyzer (Roche Diagnostics, Mannheim, Germany). We calculated free testosterone (FT) from TT and SHBG under the assumption of a constant albumin concentration of 4.3 mg/ml, according to Vermeulen et al (22). Free androgen index (FAI) was determined as testosterone (nmol/l) ⫻ 100/SHBG (nmol/l). The lipid profile including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride was assessed for each patient by using automatic clinical chemistry analyzer (Hitachi 7600 D and P model, Japan). The women were screened for diabetes and insulin resistance; only those with serum fasting glucose ⬍ 100 mg/dl and homeostatic model assessment-insulin resistance (HOMAIR)⬍2.4 were included in this study. HOMAIR index was calculated as HOMAIR ⫽ fasting insulin (␮IU/ml)⫻ fasting glucose (mmol/l)/22.5.

Ultrasound evaluation All subjects underwent a transvaginal ultrasound scan, which was performed by a single investigator using a Voluson E8 (GE Healthcare, Buckinghamshire, UK) and a 5–9-MHz transvaginal probe with both 3D and 4D scanning modes. Sonographic data were obtained on day 2 or 3 after the onset of menstrual bleeding to ensure that no underlying pathological condition existed and to determine the antral follicle count. Antral follicles were measured in the rendered view after the ovary had been defined using

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doi: 10.1210/jc.2013-3873

virtual organ computer-aided analysis (VOCAL, GE Healthcare). After the application of inversion mode, antral follicles were counted by rotating the resultant display through 180°.

Statistical analysis Association between 25(OH)D and steroid hormones was analyzed by multiple linear regression, with potential confounders analyzed by partial correlation. We used spline regression analysis to further clarify the nonlinear curvature association and identify a possible threshold on the curve. A threshold was indicated at the spline knot where the slope attenuates. Pearson correlation analysis was used to determine associations between 25(OH)D and ovarian reserve biomarkers. Statistical significance was set at P ⬍ .05. Bonferroni correction was applied to decrease the potential of an alpha error by multiple hypothesis testing. All statistical analyses were conducted using IBM SPSS software 20 (SPSS Inc., Chicago, IL).

Results The mean age of the 73 participants was 33.8 years(range 27–38), and mean body mass index (BMI) was 20.7 kg/m2 (range 15.9 –26.1). Because blood was drawn from these urban residents only in winter, the proportion of the study cohort with vitamin D insufficiency was higher (94.4% vs. 64.5%) and mean 25(OH)D concentration lower (10.47 ⫾ 4.58 vs. 18.2 ⫾ 7.1 ng/ml) than national data, which included specimens obtained throughout the year from 3,878 females ⱖ 10 years old from all 16 administrative districts of South Korea (23). Baseline characteristics of participants are shown in Table 1. The relationship between serum levels of 25(OH)D and E2, TT, FT, FAI, and DHEAS was analyzed by linear regression without adjusting for covariates (model 1), after adjusting for age and BMI (model 2), and after adjusting for age, BMI, HOMAIR, SHBG and lipid profile (model 3) (Table 2). In the unadjusted model, serum 25(OH)D level was positively associated with E2 (P ⫽ .049), TT (P ⫽ .001), FT (P ⫽ .008), and FAI (P ⬍ .001). After adjusting for potential confounders, these associations remained largely unchanged, except that an independent relationship was no longer observed between 25(OH)D and E2. Regarding vitamin D as a regulator of testosterone level, results of linear regression analysis showed that each additional 1ng/ml 25(OH)D increased TT by 1.241 ng/dl (P ⬍ .001). With spline regression models, curved linear correlation was observed which showed near plateau (␤ coefficient 0.173, 95% CI – 0.535– 0.881) until 25(OH)D level of 13ng/dl where slop attenuates thereafter (␤ coefficient 2.374, 95% CI 1.435–3.313). Serum 25(OH)D level was not associated with LH (P ⫽ .511),17a-hydroxyprogesterone (P ⫽ .664), or DHEAS (P ⫽ .140) levels. Among the ovarian reserve biomarkers tested, antiMüllerian hormone (AMH) showed high intercorrelation

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with antral follicle count (r⫽0.454, P ⬍ .001), FSH (r⫽0.327, P ⫽ .005), and ovarian volume (right ovary: r⫽0.398, P ⫽ .001;left ovary: r⫽0.412, P ⫽ .001). However, 25(OH)D did not correlate with AMH (r⫽0.001, P ⫽ .991) or other ovarian reserve markers (Table 3).

Discussion In this study we demonstrated a novel independent relationship between serum 25(OH)D and testosterone levels in healthy fertile women. The effect of testosterone on male reproduction has been extensively studied, and considerable evidence supports the influence of vitamin D on semen quality through the regulation of calcium metabolism and testosterone production (24). However, few studies have focused on the effects of testosterone in women, and the relationship between testosterone and vitamin D levels in healthy women has not been previously reported. Our study found that increased serum vitamin D level was associated with increased TT and FAI but was not associated with other sex hormones or various ovarian reserve markers. The effect of vitamin D on TT level may be directly due to increased ovarian/adrenal production of testosterone and/or increased transformation of the precursor steroids DHEA-S and DHEA in peripheral tissues (25). Our study demonstrated a positive relationship between 25(OH)D and testosterone level but no relationship between 25(OH)D and DHEAS level, suggesting that 25(OH)D increased ovarian production of testosterone or peripheral conversion of DHEAS to testosterone, rather than decreasing adrenal production. Increase in testosterone could operate via indirect pathway as demonstrated by the stimulatory effect of the osteoblast-derived hormone osteocalcin on testosterone production in mice and men from the general population (26). Our result differs from recent report of a negative association between vitamin D status and hyperandrogenism in women with polycystic ovary syndrome (PCOS), however a later study suggested that this effect may be due to a reduction in SHBG that results from obesity (4). The clinical significance of our study is that this relationship between 25(OH)D and testosterone levels in women may partially explain the beneficial effect of vitamin D on reproductive outcomes. Subanalysis of our study have shown that 25(OH)D level reaching above 13ng/dl is associated with significantly improved testosterone production. Although often undiagnosed, testosterone insufficiency can lead to various health problems in women and mimics menopause, with symptoms such as decreased libido, vaginal dryness, mood changes, hot flashes, sleep

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Testosterone level is associated with vitamin D status

Table 1.

J Clin Endocrinol Metab

Baseline characteristics of the study population (*n ⫽ 73) Variables Age (years) Body mass index (kg/m2) Systolic/ Diastolic blood pressure (mmHg) 25(OH)D concentration (ng/mL) Total antral follicle count (number) Ovarian volume, right/left (cm3) AMH (ng/ mL) FSH (mIU/ mL) LH (mIU/ mL) E2 (pg/mL) P (ng/mL) TT (ng/dL) Free testosterone (pg/mL) Free androgen index DHEAS (ug/dL) HOMA index Total cholesterol (mg/dL) TG (mg/dL) HDL (mg/ dL) LDL (mg/ dL)

Mean (SD) 33.8 (2.9) 20.7 (2.0)

116 (11.8) /72 (8.6)

10.3 (4.6)

15.4 (5.5)

4.6 (1.9) /4.1 (1.9)

4.6 (2.5) 7.9 (2.3) 3.0 (2.3) 26.6 (16.3) 0.6 (0.2) 10.7 (9.2) 1.4 (1.3)

0.6 (0.5)

140.2 (52.8) 0.9 (0.5) 166.4 (30.5)

74.3 (24.7) 56.9 (11.5) 97.6 (23.7)

25(OH)D, 25-hydroxyvitamin D; AMH, Anti-Müllerian hormone; FSH, follicle-stimulating hormone; E2, estradiol; P,17␣-hydroxyprogesterone; TT, total testosterone; FT, free testosterone; FAI, free androgen index; DHEAS, dehydroepiandrosterone sulfate; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; *None of the participants were current smoker or having any supplement intake.

disturbances, decreased muscle mass, and low bone density leading to osteoporosis (25, 27). Testosterone appears to stimulate follicle maturation with positive effects on reproductive outcomes (28) and androgen accumulation in the primate ovary is important in early follicular development and granulosa cell proliferation (29). Ovarian tes-

tosterone, which decreases with age, increases antral follicle response to stimulation, and its effects are mediated or potentiated by FSH receptor activity and insulin like growth factor 1(30). In assisted reproduction technique, basal level of serum testosterone was associated with ovarian response and in vitro fertilization (IVF) outcome in

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doi: 10.1210/jc.2013-3873

Table 2.

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Association of 25(OH)D with steroid hormone: linear regression analysis

Dependent variables E2 TT FT FAI DHEAS

25(OH)D Model 1 0.802 ⫾ 0.418(0.049)* 1.241 ⫾ 0.188(⬍0.001)** 0.006 ⫾ 0.002 (0.008)** 0.044 ⫾ 0.011 (⬍0.001)** -2.038 ⫾ 1.367 (0.140)

Model 2 0.739 ⫾ 0.424 (0.086) 1.215 ⫾ 0.193 (⬍0.001)** 0.005 ⫾ 0.002 (0.018)* 0.039 ⫾ 0.011 (0.001)** -2.178 ⫾ 1.406 (0.126)

Model 3 0.513 ⫾ 0.443 (0.252) 1.233 ⫾ 0.217 (⬍0.001)** 0.005 ⫾ 0.002 (0.034)* 0.043 ⫾ 0.011 (⬍0.001)** -1.554 ⫾ 1.480 (0.3298)

Model 1, unadjusted; Model 2, adjusted for age and BMI; Model 3, adjusted for age, BMI, HOMAIR, SHBG, and lipid profile(total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein). E2, estradiol; TT, total testosterone; FT, free testosterone; FAI, free androgen index; DHEAS, dehydroepiandrosterone sulfate. *P ⬍ 0.05, ** Nominally significant after Bonferroni correction;data are presented as estimate ⫾ standard error (P value).

Table 3.

Correlation analysis between serum 25(OH)D level and markers of ovarian reserve.

AMH FSH AFC Ovarian volume(R) Ovarian volume(L)

25(OH)D

AMH

FSH

AFC

0.001 (0.991) -0.101 (0.399) 0.066 (0.606) -0.097 (0.451)

-0.327 (0.005) ** 0.454 (⬍0.001) ** 0.398 (0.001) **

-0.198 (0.120) -0.279 (0.027) *

0.505 (⬍0.001) **

0.075 (0.563)

0.412 (0.001) **

-0.397 (0.001) **

0.361 (0.004) **

Ovarian volume(R)

0.314 (0.013) *

AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; AFC, antral follicle count; R, right; L, left. *P ⬍ 0.05, Nominally significant after Bonferroni correction; data are presented as r (P value).

women with diminished ovarian reserve (31). Additionally, continuous positive correlation of free androgen index to total ovarian follicle count following ovarian stimulation was reported in non-PCOS patients (32). Taken together, these findings may indicate that sufficient vitamin D levels may enhance fertility potential by increasing testosterone levels. Relationship between estrogen and vitamin D existed only before adjustment which means there is no individual relationship between E2 and 25(OH)D in our study population. Ovaries continue to secrete high levels of estrogen until late reproductive age (33) and numerous factors are involved in the regulation of estrogen levels; therefore, it is not surprising that vitamin D status was not associated with E2 level in our study cohort of healthy fertile women. Because E2 levels are high in women, any effect of vitamin D status may be small, whereas testosterone, which is produced at lower levels, may be affected by even a subtle change in vitamin D status. A number of animal and human studies have previously suggested that vitamin D is a regulator of AMH expression and ovarian reserve. For example, a study of prostate cancer suggested that 1,25(OH)2D3 inhibits the growth of prostate cancer cells through the vitamin D response element in the AMH gene, which has been shown to be directly regulated by 1,25(OH)2D3 (34, 35). Similarly, AMH expression in granulosa cells of the hen is regulated by vitamin D (36). Although a recent cohort study conducted in the US reported that circulating 25(OH)D3 was

**

positively correlated with serum AMH levels in women of late reproductive age (⬎40 years old), we failed to observe any relationship between AMH and 25(OH)Dlevels in our study (20). Moreover, vitamin D level did not correlate with the other ovarian function reserve markers tested. Possible explanations for these discrepant results include differences in geographic location, ethnicity, and vitamin D status of the study populations. Regarding that vitamin D level in current study population was lower compared to national data, further study is warranted in a population with adequate vitamin D levels. In addition, participants in the current study were healthy 28- to 37-year-old parous women with normal ovarian function, whereas the cohort of the previous study consisted of HIV-seropositive, high-risk patients. Although decreased vitamin D levels have been reported in women with premature ovarian failure, this does not appear to be a causal relationship because a recent study reported that vitamin D levels were similar in early and late menopause (21, 37). It is noteworthy that AMH levels fluctuate according to the season and stage of the menstrual cycle (38, 39). A recent interventional study of 33 premenopausal women (19 –39 years old) showed that individual variability of AMH level was associated with the extent to which 25(OH)D levels varied, and vitamin D3 supplementation blocked seasonal changes in both 25(OH)D and AMH levels (40). Thus, vitamin D status may be seasonally covariant with AMH level. Although the therapeutic use of androgen to increase

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Testosterone level is associated with vitamin D status

ovarian response during IVF is controversial, a recent meta-analysis concluded that transdermal testosterone pretreatment improves clinical pregnancy and live birth rates, whereas no beneficial effect was detected in poor responders treated with DHEA (41). Another study reported that the benefits of DHEA in IVF were associated with the efficiency of androgen conversion from DHEA to testosterone and the amplitude of testosterone gain, rather than DHEA itself (28). We believe that adequate vitamin D levels may boost androgen production, resulting in a beneficial increase in testosterone level. Thus, large prospective dose-response studies are warranted to confirm beneficial effect of vitamin D supplementation in patient preparing for IVF. Since recent interventional studies have reported that vitamin D can prevent adverse pregnancy and neonatal outcomes; vitamin D supplementation may be readily accepted by women planning to become pregnant (3). Certain limitations are inherent in our study. Given its cross sectional design, we cannot determine whether a causal relationship exists between vitamin D status and testosterone level. Additionally, since our study included small number of healthy population with relatively low mean level of vitamin D, it is insufficient to generalize to all women or to establish optimal threshold. Moreover, there could be other malabsorption and nutritional effect influencing the level of testosterone more than vitamin D. However, the main strengths of our study are the strict eligibility criteria, collection of blood specimens in winter only and use of multivariate analysis to reduce possible confounding factors that might effect on revealing independent relationship. In conclusion, this is first study to show that vitamin D status correlates with testosterone level in healthy nonobese women. Our finding suggests that vitamin D may increase fertility through the modulation of androgen activity. In the light of our finding, in vitro and in vivo experimental studies must be carried out to determine the molecular mechanisms underlying the effect of vitamin D on testosterone level. Additionally, interventional studies are needed to confirm a direct cause-and-effect relationship between vitamin D and testosterone levels and to evaluate the potential therapeutic benefits of vitamin D supplementation on reproductive outcomes.

Acknowledgments The present study was supported by a grant (A120080) from the Korean Healthcare Technology R&D project, Ministry for Health, Welfare and Family Affairs, Republic of Korea.

J Clin Endocrinol Metab

Address all correspondence and requests for reprints to: Woo Sik Lee, M.D., Ph.D., Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, 650 –9 Yeoksam, Gangnamgu, Seoul 135– 081, Republic of Korea. Tel: ⫹82–2–3468 –3403, Fax: ⫹82–2–3468 –3464, E-mail: [email protected]. Disclosure Summary: No author has a conflict of interest. This work was supported by a grant (A120080) from the Korean Healthcare Technology R&D project, Ministry for Health, Welfare and Family Affairs, Republic of Korea.

References 1. Mellanby E. An experimental investigation on rickets. 1919. Nutrition 5:81– 86; discussion 87. 2. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266 – 281. 3. Hossein-Nezhad A, Holick MF. Vitamin d for health: a global perspective. Mayo Clin Proc. 2013;88:720 –755. 4. Thomson RL, Spedding S, Buckley JD. Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2012;77:343–350. 5. Hossein-nezhad A, Holick MF. Optimize dietary intake of vitamin D: an epigenetic perspective. Curr Opin Clin Nutr Metab Care. 2012;15:567–579. 6. Shand AW, Nassar N, Von Dadelszen P, Innis SM, Green TJ. Maternal vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre-eclampsia. BJOG. 2010;117: 1593–1598. 7. Luk J, Torrealday S, Neal Perry G, Pal L. Relevance of vitamin D in reproduction. Hum Reprod. 2012;27:3015–3027. 8. Wayne NL, Malpaux B, Karsch FJ. Photoperiodic requirements for timing onset and duration of the breeding season of the ewe: synchronization of an endogenous rhythm of reproduction. J Comp Physiol A. 1990;166:835– 842. 9. Cummings DR. Human birth seasonality and sunshine. Am J Hum Biol. 2010;22:316 –324. 10. Lam DA, Miron JA. Seasonality of births in human populations. Soc Biol. 1991;38:51–78. 11. Smith DM, Conaway CH, Kerber WT. Influences of season and age on maturation in vitro of rhesus monkey oocytes. J Reprod Fertil. 1978;54:91–95. 12. Rojansky N, Benshushan A, Meirsdorf S, Lewin A, Laufer N, Safran A. Seasonal variability in fertilization and embryo quality rates in women undergoing IVF. Fertil Steril. 2000;74:476 – 481. 13. Stolwijk AM, Reuvers MJ, Hamilton CJ, Jongbloet PH, Hollanders JM, Zielhuis GA. Seasonality in the results of in-vitro fertilization. Hum Reprod. 1994;9:2300 –2305. 14. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, Masushige S, Fukamizu A, Matsumoto T, Kato S. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16:391–396. 15. Halloran BP, DeLuca HF. Effect of vitamin D deficiency on fertility and reproductive capacity in the female rat. J Nutr. 1980;110:1573– 1580. 16. Dent CE, Harris H. Hereditary forms of rickets and osteomalacia. J Bone Joint Surg Br. 1956;204 –226. 17. Ott J, Wattar L, Kurz C, Seemann R, Huber JC, Mayerhofer K, Vytiska-Binstorfer E. Parameters for calcium metabolism in women with polycystic ovary syndrome who undergo clomiphene citrate stimulation: a prospective cohort study. Eur J Endocrinol. 2012; 166:897–902. 18. Ozkan S, Jindal S, Greenseid K, Shu J, Zeitlian G, Hickmon C, Pal

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doi: 10.1210/jc.2013-3873

19.

20.

21.

22.

23.

24. 25.

26. 27. 28.

29.

30.

L. Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertil Steril. 2010;94:1314 –1319. Parikh G, Varadinova M, Suwandhi P, Araki T, Rosenwaks Z, Poretsky L, Seto-Young D. Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm Metab Res. 2010;42:754 –757. Merhi ZO, Seifer DB, Weedon J, Adeyemi O, Holman S, Anastos K, Golub ET, Young M, Karim R, Greenblatt R, Minkoff H. Circulating vitamin D correlates with serum antimullerian hormone levels in late-reproductive-aged women: Women’s Interagency HIV Study. Fertil Steril. 2012;98:228 –234. Kebapcilar AG, Kulaksizoglu M, Kebapcilar L, Gonen MS, Unlü A, Topcu A, Demirci F, Taner CE. Is there a link between premature ovarian failure and serum concentrations of vitamin D, zinc, and copper? Menopause. 2013;20:94 –99. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666 –3672. Choi HS, OH HJ, Choi H, Choi WH, Kim JG, Kim KM, Kim KJ, Rhee Y, Lim SK. Vitamin D insufficiency in Korea-a greater threat to younger generation: the Korea National Health and Nutrition Examination Survey (KNHANES). J Clin Endocrinol Metab. 2008; 96:643– 651. Blomberg Jensen M. Vitamin D metabolism, sex hormones, and male reproductive function. Reproduction. 2012;144:135–152. Pluchino N, Carmignani A, Cubeddu A, Santoro A, Cela V, Alcala TE. Androgen therapy in women: for whom and when. Arch Gynecol Obstet. 2013;288:731–737. Karsenty G, Oury F. Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol. 2013;382:521–526. Davis SR. Androgen therapy in women, beyond libido. Climacteric. 2013;16 Suppl 1:18 –24. Gleicher N, Kim A, Weghofer A, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH. Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR). J Assist Reprod Genet. 2013;30:49 – 62. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, Bondy CA. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab. 1998;83:2479 –2485. Qin Y, Zhao Z, Sun M, Geng L, Che L, Chen Z-J. Association of

jcem.endojournals.org

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

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basal serum testosterone levels with ovarian response and in vitro fertilization outcome. Reprod Biol Endocrinol. 2011;20:9:9. Dickerson EH, Cho LW, Maguiness SD, Killick SL, Robinson J, Atkin SL. Insulin resistance and free androgen index correlate with the outcome of controlled ovarian hyperstimulation in non-PCOS women undergoing IVF. Hum Reprod. 2010;25:504 –509. Meldrum DR, Chang RJ, Giudice LC, Balasch J, Barbieri RL. Role of decreased androgens in the ovarian response to stimulation in older women. Fertil Steril. 2013;99:5–11. Burger HG, Hale GE, Robertson DM, Dennerstein L. A review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women’s Midlife Health Project. Hum Reprod Update. 2007;13:559 –565. Krishnan AV, Moreno J, Nonn L, Malloy P, Swami S, Peng L, Peehl DM, Feldman D. Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer. J Steroid Biochem Mol Biol. 2007;103:694 –702. Malloy PJ, Peng L, Wang J, Feldman D. Interaction of the vitamin D receptor with a vitamin D response element in the Mullerianinhibiting substance (MIS) promoter: regulation of MIS expression by calcitriol in prostate cancer cells. Endocrinology. 2009;150: 1580 –1587. Wojtusik J, Johnson PA. Vitamin D regulates anti-Mullerian hormone expression in granulosa cells of the hen. Biol Reprod. 2012; 86:91. Lee MK, Yoon BK, Chung HY, Park HM. The serum vitamin D nutritional status and its relationship with skeletal status in Korean postmenopausal women. Obstet Gynecol Science. 2011;54:241– 246. Hadlow N, Longhurst K, McClements A, Natalwala J, Brown SJ, Matson PL. Variation in antimullerian hormone concentration during the menstrual cycle may change the clinical classification of the ovarian response. Fertil Steril. 2013;99:1791–1797. Roudebush WE, Nethery RA, Heldreth T. Presence of anti-mullerian hormone in the squirrel monkey (Saimiri boliviensis): gender and seasonal differences. J Med Primatol. 2013;42:15–19. Dennis NA, Houghton LA, Jones GT, van Rij AM, Morgan K, McLennan IS. The level of serum anti-Mullerian hormone correlates with vitamin D status in men and women but not in boys. J Clin Endocrinol Metab. 2012;97:2450 –2455. Bosdou JK, Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG, Zepiridis L, Tarlatzis BC. The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2012; 18:127–145.

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Association between sex steroids, ovarian reserve, and vitamin D levels in healthy nonobese women.

Vitamin D maintains calcium and phosphorous homeostasis and promotes bone mineralization; however, its nonskeletal functions are increasingly being re...
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