Marika Lundqvist

RE: Is There a Correlation Between Androgens and Sexual Desire in Women?

We were very interested to read the results of the study by WåhlinJacobsen et al. [1] titled “Is there a correlation between androgens and sexual desire in women?” The researchers used mass spectrometry methods to investigate age-adjusted serum levels of dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and testosterone, as well as androsterone glucuronide (ADT-G)—a measure of total androgen activity. The results were consistent with our published study of 121 women with and 124 women without a diagnosis of Hypoactive Sexual Desire Disorder (using the definition of the Diagnostic and Statistical Manual, 4th edition, text-revised), where no group differences in androgen metabolites were found [2]. We were somewhat perplexed by the apparent change in Wåhlin-Jacobsen et al.’s [1] objective in their paper from investigating a possible correlation between serum levels of testosterone and/or androgen metabolites and sexual desire, to finding a measure that does indeed correlate with desire and to apparently suggest its use hereon. The conclusion in the abstract that ADT-G did not correlate more strongly than circulating androgens with sexual desire and therefore is not superior to measuring circulating androgens with mass spectrometry presupposes an established correlation between androgens and sexual desire. The authors note that “measuring the degradation product of the intracellular testosterone turnover should therefore yield a better estimate of both the intracellular turnover and the total activity of androgens. In contrast to what we expected, however, no statistically significant correlations were established between ADT-G and sexual desire. Therefore, based on these current and previous results, we cannot conclude that ADT-G is a better biomarker of the link between androgens and women’s sexual desire than measuring the amount of circulating androgens.” (p. 12). An explanation for these findings can, however, be based upon the understanding that the metabolite of androgens chosen as a parameter of total androgenic activity, namely ADT-G, although a logical suggestion, could have to take into account a more complex pattern than originally believed [3]. As mentioned by the authors, it could well be that ADT-G represents only a fraction of all androgen metabolites. In fact, it could be that ADT-sulfate and epi-ADT-G (and likely others) could represent a much larger proportion of androgen metabolites than ADT-G alone. However, since the very low serum levels of testosterone observed in women during their whole life essentially result from some leakage of the intracellular testosterone synthesized locally from DHEA [4], it might be reasonable, at the present time, to measure the precursors of intracellular testosterone, namely serum DHEA, DHEA-S, androstene-3β,17β-diol, and androstenedione. In fact, low serum levels of all these four androgen precursors have been correlated with sexual dysfunction [1,2,5]. The authors did find a correlation between total testosterone, free testosterone, androstenedione, and DHEA-S in the subgroup of women aged 25–44 who were not using any hormonal contraception (n = 168). In our study, 246 women were more stringently recruited to exclude confounds such as any medication potentially altering sexual response and desire, scoring in the clinically significant depressed range on a validated measure of depression, significant relationship conflict, and sexual pain, and this study failed to show a correlation between mass spectrometry-measured serum testosterone and desire but showed a correlation with low serum DHEA-S [2]. We maintain our conclusion [2] that in large samples of women, there is not yet conclusive evidence of a significant correlation between accurately measured total testosterone activity and sexual desire. This is not to say androgen activity may not be important, but at this point, such evidence of a correlation has not been empirically supported. As indicated above, it could well be that serum testosterone is not a reliable marker since it represents only leakage of intracellular testosterone made by the intracellular mechanisms of intracrinology [4]. The conclusion of Wåhlin-Jacobsen et al. [1] that as measurement of ADT-G showed no significant correlation with women’s sexual desire, such measurement “did not seem to be an improvement over measuring circulating androgens with MS” (p. 14) suggests that there was a very different a priori objective to the study than what was published. A recent editorial reminds us of the significant dangers inherent to modification of a priori hypotheses and the threat to statistical analyses as well as interpretation of the findings [6]. That the identification/measurement of the most appropriate metabolites of androgens has not yet been determined in no way negates the importance of intracellular testosterone production. We offer this analogy: the hypothetical investigation of a correlation between intake of vitamin C supplements and susceptibility to influenza. Imagine researchers counting vitamin C supplements taken by patients and finding the numbers to correlate negatively with number of influenza infections. However, when measuring their serum vitamin C levels, no correlation is found between vitamin C levels and cases of influenza. If the researchers then said “from here-on just count vitamin C supplements as this correlates better with influenza susceptibility,” perhaps the lack of a scientific demonstration would be more obvious. In summary, with the strong caveat of relatively lax exclusion criteria, the findings by Wåhlin-Jacobsen et al. have added to the literature on women’s sexual desire and androgens, which are based on the currently available most optimal assays for serum androgens and precursor hormones (liquid chromatography-mass spectrometry), and for total (intracellular plus serum) androgens (ADT-G). As in our study [2], precursors of intracellular testosterone correlated with sexual desire in women aged 25–65 years, none of whom were taking systemic sex hormones. In contrast to our study, in the subgroup of 168 women aged 25–45 years, desire also correlated with measures of serum testosterone. It will be important to repeat these measures on this targeted subgroup, but with stricter exclusion criteria as well as the entry criterion of a diagnosis of sexual interest/arousal disorder assessed by detailed interview as currently available questionnaires do not reflect current conceptualization of women’s sexual response or current 1

Vitamin D Status during Pregnancy and the Risk of Subsequent Postpartum Depression: A Case-Control Study

Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations < 15 nmol/L, 15–24 nmol/L and 25–49 nmol/L, respectively, and 1.53 (CI: 1.04; 2.26) and 1.89 (CI: 1.06; 3.37) among women with vitamin D concentrations of 80–99 nmol/L and ≥ 100 nmol/L, respectively. In an additional analysis among women with sufficient vitamin D (≥ 50 nmol/L), we observed a significant positive association between vitamin D concentrations and PPD. Our results did not support an association between low maternal vitamin D concentrations during pregnancy and risk of PPD. Instead, an increased risk of PPD was found among women with the highest vitamin D concentrations.

Neonatal vitamin D status and risk of multiple sclerosis A population-based case-control study

Objective: As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS. Methods: We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models. Results: We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36–0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57–0.84). Conclusion: Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.

Decrease in vitamin D status in the Greenlandic adult population from 1987-2010.

Background Low vitamin D status may be pronounced in Arctic populations due to limited sun exposure and decreasing intake of traditional food. Objective To investigate serum 25(OH)D3 as a measure of vitamin D status among adult Inuit in Greenland, predictors of low serum 25(OH)D3 concentrations and the trend from 1987 to 2005–2010. Design A total of 2877 randomly selected Inuit (≥18 years) from the Inuit Health in Transition study were included. A sub-sample (n = 330) donated a blood sample in 1987 which allowed assessment of time trends in vitamin D status. Results The geometric mean serum 25(OH)D3 (25[OH]D2 concentrations were negligible and not reported) in 2005–2010 was lowest among the 18–29 year old individuals (30.7 nmol/L; 95% CI: 29.7; 31.7) and increased with age. In all age-groups it decreased from 1987 to 2005–2010 (32%–58%). Low 25(OH)D3 concentrations (<50 nmol/L) were present in 77% of the 18–29 year old and decreased with age. A characteristic seasonal variation in 25(OH)D3 concentrations was observed (range 33.2–57.1 nmol/L, p<0.001), with the highest concentrations in August to October. Age (2.0% per year increase; CI: 1.7, 2.2), female gender (7.1%; CI: 2.0; 12.5), alcohol intake (0.2% per increase in drinks/week; 0.0; 0.4), and traditional diet (10.0% per 100 g/d increase; CI: 7.9; 12.1) were associated with increased serum 25(OH)D3, whereas smoking (−11.6%; CI: −16.2; −6.9), BMI (−0.6%; CI: −1.1; −0.2) and latitude (−0.7% per degree increase; CI: −1.3; −0.2) were associated with decreased concentrations. Conclusion We identified a remarkable decrease in vitamin D status from 1987 to 2005–2010 and a presently low vitamin D status among Inuit in Greenland. A change away from a traditional diet may well explain the observed decline. The study argues for the need of increased dietary intake of vitamin D and supplementation might be considered.

Associations between Vitamin D Status and Type 2 Diabetes Measures among Inuit in Greenland May Be Affected by Other Factors.

Objective Epidemiological studies have provided evidence of an association between vitamin D insufficiency and type 2 diabetes. Vitamin D levels have decreased among Inuit in Greenland, and type 2 diabetes is increasing. We hypothesized that the decline in vitamin D could have contributed to the increase in type 2 diabetes, and therefore investigated associations between serum 25(OH)D3 as a measure of vitamin D status and glucose homeostasis and glucose intolerance in an adult Inuit population. Methods 2877 Inuit (≥18 years) randomly selected for participation in the Inuit Health in Transition study were included. Fasting- and 2hour plasma glucose and insulin, C-peptide and HbA1c were measured, and associations with serum 25(OH)D3 were analysed using linear and logistic regression. A subsample of 330 individuals who also donated a blood sample in 1987, were furthermore included. Results After adjustment, increasing serum 25(OH)D3 (per 10 nmol/L) was associated with higher fasting plasma glucose (0.02 mmol/L, p = 0.004), 2hour plasma glucose (0.05 nmol/L, p = 0.002) and HbA1c (0.39%, p<0.001), and with lower beta-cell function (-1.00 mmol/L, p<0.001). Serum 25(OH)D3 was positively associated with impaired fasting glycaemia (OR: 1.08, p = 0.001), but not with IGT or type 2 diabetes. Conclusions Our results did not support an association between low vitamin D levels and risk of type 2 diabetes. Instead, we found weak positive associations between vitamin D levels and fasting- and 2hour plasma glucose levels, HbA1c and impaired fasting glycaemia, and a negative association with beta-cell function, underlining the need for determination of the causal relationship.

Sun Exposure Guidelines and Serum Vitamin D Status in Denmark: The StatusD Study

Little is known on how vitamin D status is affected by adherence to UVB-limiting sun exposure guidelines. Our aim was to investigate the relationship between adherence to the Danish sun exposure guidelines and vitamin D status. In total, 3194 Danes (2625 adults, 569 children) were recruited among the general population, and more than 92% had blood samples taken both autumn and spring. Using linear regression, we associated serum vitamin D concentrations to questionnaire responses on: seeking shade, wearing a sunhat, wearing protective clothing or using sunscreen. The odds ratio (OR) of either low (<25 or 50 nmol/L) or adequate/high (≥50 nmol/L) vitamin D status was examined using logistic regression. For adults, those who always sought shade or wore protective clothing compared to those who did not had lower levels of vitamin D (autumn concentrations for shade: 7.2 nmol/L lower (−11.0–−3.6 nmol/L); for protective clothing: 9.9 nmol/L lower (−13.6–−6.2 nmol/L). Adherence to all four guidelines was also associated with lower vitamin D concentrations (autumn: 9.7 nmol/L lower (−14.3–−5.1 nmol/L). Use of sunscreen was associated with adequate vitamin D status, as those who always sought shade compared to those who did not had an OR (95% CI) of 1.68 (1.25–2.35) of having ≥50 nmol/L during both spring and autumn. No associations were found with wearing a sunhat, and there were no clear associations for children. In conclusion, adherence to the sun exposure guidelines on shade and protective clothing was associated with lower vitamin D status among Danish adults, but not children.

Maternal and neonatal vitamin D status, genotype and childhood celiac disease

Background Low concentration of 25-hydroxyvitamin D during pregnancy may be associated with offspring autoimmune disorders. Little is known about environmental triggers except gluten for celiac disease, a common immune-mediated disorder where seasonality of birth has been reported as a risk factor. We therefore aimed to test whether low maternal and neonatal 25-hydroxyvitamin D predicted higher risk of childhood celiac disease. Methods and Findings In this Norwegian nationwide pregnancy cohort (n = 113,053) and nested case-control study, we analyzed 25-hydroxyvitamin D in maternal blood from mid-pregnancy, postpartum and cord plasma of 416 children who developed celiac disease and 570 randomly selected controls. Mothers and children were genotyped for established celiac disease and vitamin D metabolism variants. We used mixed linear regression models and logistic regression to study associations. There was no significant difference in average 25-hydroxyvitamin D between cases and controls (63.1 and 62.1 nmol/l, respectively, p = 0.28), and no significant linear trend (adjusted odds ratio per 10 nM increase 1.05, 95% CI: 0.93–1.17). Results were similar when analyzing the mid-pregnancy, postpartum or cord plasma separately. Genetic variants for vitamin D deficiency were not associated with celiac disease (odds ratio per risk allele of the child, 1.00; 95% CI, 0.90 to 1.10, odds ratio per risk allele of the mother 0.94; 95% CI 0.85 to 1.04). Vitamin D intake in pregnancy or by the child in early life did not predict later celiac disease. Adjustment for established genetic risk markers for celiac disease gave similar results. Conclusions We found no support for the hypothesis that maternal or neonatal vitamin D status is related to the risk of childhood celiac disease.

Lack of Association Between Maternal or Neonatal Vitamin D Status and Risk of Childhood Type 1 Diabetes: A Scandinavian Case-Cohort Study

Studies on vitamin D status during pregnancy and risk of type 1 diabetes mellitus (T1D) lack consistency and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration, based on serial samples from the first trimester until delivery and on umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10-nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Neonatal Vitamin D Levels in Relation to Risk of Overweight at 7 Years in the Danish D-Tect Case-Cohort Study

Background: Vitamin D level in pregnancy may be associated with risk of overweight in the offspring later in life. Methods: In a case-cohort study based on Danish biobanks and registers we examined the association between 25-hydroxy-vitamin D (25(OH)D) level at birth and overweight at 7 years. Cases of overweight (n = 871) were randomly selected among 7-year-old children from the Copenhagen School Health Records Register (CSHRR) with a BMI above the 90th percentile. The cohort (n = 1,311) was a random sample selected among all Danish children born during the same period. Neonatal 25(OH)D was measured in dried blood spots. Results: 25(OH)D3 exhibited the expected seasonal variation. Median level of 25(OH)D3 was 20.6 (11.9-33.3) nmol/l in the overweight group and 23.4 (13.5-34.3) nmol/l in the cohort. We found no association between neonatal 25(OH)D3 level and risk of overweight at age 7 years, neither in the crude model (OR (CI) 1.00 (0.99; 1.00)) nor in a model adjusted for maternal ethnicity, educational level, civil status, parity, season and year of birth, and offspring ponderal index (OR (CI) 1.00 (0.99; 1.01)). Conclusion: Risk of overweight at 7 years of age was not associated with vitamin D level at birth.

Perinatal vitamin D levels are not associated with later risk of developing pediatric-onset inflammatory bowel disease: a Danish case-cohort study

ABSTRACT Objective Basic and epidemiologic studies on inflammatory bowel disease (IBD) have suggested an association between vitamin D and IBD risk. Though, the literature on IBD – especially pediatric-onset IBD – and vitamin D is still in its cradle. We therefore wanted to examine if levels of 25(OH)D at birth were associated with increased risk of developing pediatric-onset IBD. Material and methods A case-cohort study composed of cases diagnosed with Crohn’s disease, ulcerative colitis or indeterminate/unclassified colitis and healthy controls. Cases and controls were matched on date of birth and were born in the period 1981–2004. Cases were diagnosed before the age of 18 years. The concentration of 25(OH)D was assessed from neonatal dried blood spots using a highly sensitive liquid chromatography tandem mass spectrometry. Odds ratios (OR) were calculated using conditional logistic regression and two-way ANOVA were used to test for season and birth year 25(OH)D variations. A total of 384 matched pairs were included in the statistical analyses. Results No significant association were found between levels of 25(OH)D and IBD risk in the adjusted model (OR [95% CI] (per 25 nmol/L increase), 1.12 [0.88; 1.42], p = 0.35). 25(OH)D levels were found to fluctuate significantly with season (p < 0.001) and year (p < 0.001). Median/Q1–Q3 values for 25(OH)D were 27.1/16.5–39.5 nmol/L for cases and 25.7/16.1–39.4 nmol/L for controls. Conclusion Our study do not suggest that a window of vulnerability exist around time of birth in regards to 25(OH)D levels and later pediatric-onset IBD risk.