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Serum androgen profiles in women with premature ovarian insufficiency

a systematic review and meta-analysis

Soman, Midhun, MS1; Huang, Li-Cong, MD1; Cai, Wen-Hui, MS1; Xu, Jun-Bi, MS1; Chen, Jun-Yao, MD1; He, Ren-Ke, MS1; Ruan, Heng-Chao, MS1,2,3; Xu, Xiang-Rong, MD1,2,3; Qian, Zhi-Da, MD1,2,3,4; Zhu, Xiao-Ming, MD, PhD1,2,3

doi: 10.1097/GME.0000000000001161
Original Articles
Open
SDC

Objective: This meta-analysis aims to investigate serum androgen profiles (testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin) in women with premature ovarian failure and to establish if there is evidence of diminished androgen levels in these women.

Methods: Various Internet sources of PubMed, Cochrane library, and Medline were searched systematically until February, 2018. Out of a pool of 2,461 studies, after applying the inclusion/exclusion criterion, 14, 8, 10, and 9 studies were chosen for testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin, respectively, for this meta-analysis. The effect measure was the standardized mean difference with 95% confidence interval (95% CI) in a random-effects model.

Results: The testosterone concentrations in premature ovarian insufficiency were compared with fertile controls: stamdard mean difference (IV, random, 95% CI) −0.73 [−0.99, −0.46], P value < 0.05. The dehydroepiandrosterone sulfate concentrations in premature ovarian insufficiency compared to fertile controls: standard mean difference (IV, random, 95% CI) −0.65 [−0.92, −0.37], P value < 0.05. Androstenedione in premature ovarian insufficiency were compared with fertile controls: standard mean difference (IV, random, 95% CI) −1.09 [−1.71, −0.48], P value < 0.05. Sex hormone-binding globulin levels did not show statistical significance. The dehydroepiandrosterone sulfate levels were reduced in premature ovarian insufficiency cases, but still showed a higher level than in postmenopausal women.

Conclusions: Women with premature ovarian insufficiency are at risk for decreased concentrations of testosterone, dehydroepiandrosterone sulfate, and androstenedione. Dehydroepiandrosterone sulfate levels were more reduced in postmenopausal controls when compared with premature ovarian insufficiency cases.

1Department of Obstetrics & Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China

2The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, P.R. China

3The Key Laboratory of Women's Reproductive Health Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China

4Department of Family Planning, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

Address correspondence to: Xiao-Ming Zhu, MD, PhD, and Zhi-Da Qian MD, Department of Obstetrics & Gynecology, Women's hospital, School of Medicine, Zhejiang University, 1 Xueshi Rd. Hangzhou, 310006 Zhejiang, P.R. China. E-mail: ntzhuxm@zju.edu.cn, qianada@zju.edu.cn

Received 29 March, 2018

Revised 18 May, 2018

Accepted 18 May, 2018

MS and L-CH contributed equally to this work.

Funding/support: None reported.

Financial disclosure/conflicts of interest: None reported.

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Premature ovarian insufficiency (POI) is defined as a decrease in ovarian function occurring before the age of 40.1-3 It is characterized by hypergonadotropicamenorrhea with estrogen deficiency.

Premature ovarian insufficiency is occasionally referred to as primary ovarian failure (POF), whereas in some situations, the conditions are not the same.1-6 Women who suffer from POI can have occasionally irregular menstrual cycles or incidental periods for a considerable length of time and may even get to conceive a child.1-6 Whereas women suffering from POF usually stop having periods and can never be pregnant, POF is generally considered as the end stage of POI.1-6

Women with POI/POF not only have a deficiency of estrogens, but they may also have loss of ovarian androgens because of the atrophy of the ovarian cortex.6-9 Androgens are thought to be one of the fundamental prerequisites for a healthy woman.7-14 A lack of androgens may lead to symptoms of sexual dysfunction, such as decreased libido, loss of sexual responsiveness, or decreased sexual arousal.7-14 Other clinical manifestations are a diminished sense of well-being, dysphoric mood, cognitive dysfunction and persistent, and unexplained loss of energy.7-14

The role of androgens in maintaining a woman's health has been receiving increasing attention, but still, there is considerable controversy relating to the role of androgens in women, and it's clinical significance.4,13-21 Be as it may, there are guidelines regarding the diagnosis of androgen deficiency and the relative androgen replacement therapy in women.4,13-21 POI/POF maybe highly suspected as a cause of clinically significant androgen deficiency.5,22-24

It has not been clear if there is a decrease in androgen levels for women with POI/POF. It is clear that, at present, the state of spontaneous POI/POF is different from the natural menopausal process.1,21-25 Many studies have shown evidence that there is a gradual decline in circulating serum androgen levels as women age and that there is no independent effect of natural menopause causing a further reduction.19,20,21,26-28

If there is indeed a clinically significant reduction in androgen levels, androgen replacement therapy could be considered to augment the standard estrogen-based hormone therapy for women with POI/POF, but this needs to be further investigated.1

Some studies have shown that there was a positive correlation between serum androgen concentration in women with POI/POF to age. POI/POF is a pathologic condition in which women have lower serum estradiol levels as compared with other women of similar age.1 It is yet to be known if women with POI/POF present with lower androgen levels when compared with menopausal women. Also, there is uncertainty as to whether POI/POF is a cause of clinically significant androgendeficiency.5,22-24 There have been many individual studies comparing the androgen levels in women with POI/POF. However, the results vary for each study due to study methods employed and the use of different assays for measurement.

This systematic review and meta-analysis aims to incorporate the data from all these studies collected using different methodologies by standardizing the unit of measurement and making use of a standardized mean difference (SMD) to calculate the overall effect, and to verify if there is indeed a significant reduction in androgen concentrations in women with POI/POF compared with a healthy control group.

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METHODS

Eligibility criteria

In this meta-analysis, all published studies in which serum androgen concentrations including total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG) were described for women with POI/POF and compared with healthy controls, were considered eligible. The predefined criteria for inclusion were as follows: POI/POF had to be defined as the disappearance of periods (amenorrhea) for the past 3 months; the disappearance of periods must have occurred even before the age of 40 is attained; in addition, the participants of the study must have had elevated follicle-stimulating hormone (FSH) levels and reduced estradiol concentrations; controls were required to be women without POI/POF. The predefined exclusion criteria were as follows: the studies were excluded if the participants had hyperandrogenemia, bilateral salpingo-oophorectomy (BSO), or gonadotoxic treatment performed after menopause; if the participants used hormone therapy, the study was excluded; studies including participants other than females were excluded; studies, which focused on chromosomally abnormal POI/POF women, were excluded; reviews, case reports, letters to the editor, and conference papers were not considered for inclusion. Only English language articles were examined. Study methodology was not considered as an exclusion criterion.

The study selection processes were carried out in two phases. First and foremost, screening of titles and abstract was done to meet the inclusion criterion by two separate researchers. The consensus among themselves resolved any disagreements.

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Search strategy

The searched databases were PubMed, Cochrane library, and Medline. The time range was inception to February, 2018. Primarily the studies were evaluated by reading the titles and abstracts. The search terms were menopause, premature, ovarian, insufficiency, failure, POI, POF, testosterone, total testosterone, DHEA-S, androstenedione, and SHBG. The search syntax for PubMed central was:(“menopause, premature”[MeSH Terms] OR (“menopause”[All Fields] AND “premature”[All Fields]) OR “premature menopause”[All Fields] OR (“premature”[All Fields] AND “ovarian”[All Fields] AND “failure”[All Fields]) OR “premature ovarian failure”[All Fields]) AND (“androgens”[All Fields] OR “androgens”[MeSH Terms] OR “androgens”[All Fields] OR “androgen”[All Fields]). The search was modified for other databases used. Reference lists of relevant review articles were searched for potentially eligible studies. When required, authors were contacted for additional information.

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Study selection

Studies were scrutinized by two reviewers independently according to the predefined inclusion-exclusion criteria. The final decisions about the included articles were made by examining the full articles.

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Quality assessment and data extraction

Two independent reviewers assessed the risk of bias with the Newcastle-Ottawa Scale for meta-analysis of observational studies.29 Newcastle-Ottawa Scale for meta-analysis of observational studies grades studies based on three factors: selection, comparability, and exposure. The criteria for these assessments were as follows: is the case definition adequate? representativeness of the cases; selection of controls; definition of controls; comparability of cases and controls based on the design or analysis; ascertainment of exposure; the same method of ascertainment for cases and controls; and nonresponse rate. Two reviewers extracted data from all eligible articles independently. Data that were collected included the year of publication, study design, country, age, body mass index (BMI), number of participants, mean and standard deviation (SD) of testosterone concentrations (ng/dL), androstenedione (ng/dL), DHEA-S (μg/mL), and SHBG (nmol/L) for both cases and controls. Selection can have a maximum of 4*s, comparability a maximum of 2*s based on the two important confounding factors. In our study, we chose age and BMI as the two factors. Exposure can have a maximum of 3*s. So, altogether, 9*s are the highest that can be obtained. The high and low score ranges are arbitrarily given. Here the lowest score was 2*s and highest was 8*s. So we used a scale of 0 to 2*s being poor quality, 3 to 5*s as fair quality, and 6 to 9*s being higher quality. A study is considered good if it can score at least 1* in each category, and more *s means better quality generally.

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Statistical analysis

In this meta-analysis, the SMD with 95% confidence intervals (CIs) were solved to determine T concentrations, A concentrations, DHEA-S, and SHBG between POI/POF cases and controls. Random-effect model (REM)30 was used to calculate the pooled effect size with 95% CI. Analyses were conducted using Revman 5.3.31 Heterogeneity among studies was assessed using chi-square and quantified with the I 2 index. If the I 2 index is 0% to 40%, it means low heterogeneity and might not be important; if the I 2 index is 30% to 60%, it means moderate heterogeneity; if the I 2 index is 50% to 90%, it means substantial heterogeneity; and if the I 2 index is 75% to 100%, it means considerable heterogeneity.32 Funnel plot and Egger's test33 were used to evaluate the existence of publication bias. A subgroup analysis was done to investigate the source of heterogeneity between studies, and sensitivity analysis with leave-one-out method was performed to assess robustness of the meta-analysis. The leave-one-out method was achieved by removing one study at a time and measuring the pooled estimate.

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Main study characteristics

Various system searches resulted in 2,464 studies discussing POI/POF. The duplicate of the studies was eliminated by use of reference manager; this yielded 1,621 studies. By use of selection criteria, abstract, and screening of the title generated in the differentiation of 192 studies, text papers were retrieved from this search and were analyzed by the selection criteria. During the full-text review, 178 articles were removed. Out of them, 98 studies were removed from the list of studies because of not fulfilling the inclusion criteria. An additional 80 studies were removed from the list of studies because POI/POF diagnosis failed to meet prescribed standards. Finally, 14 studies were included for this meta-analysis (Fig. 1). Out of these 14 studies, 14, 8, 10, and 9 studies were included for total T, DHEA-S, A, and SHBG, respectively. Study characteristics for each androgen are mentioned in Tables 1-4.

FIG. 1

FIG. 1

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 3

TABLE 3

TABLE 4

TABLE 4

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Measurement of risk bias

The risk of bias assessment for studies selected for the comparison of androgen concentrations in POI/POF versus controls is reported in Table 5 [see Table, Supplemental Digital Content 1, http://links.lww.com/MENO/A333]. All the studies had clearly defined selection criteria for the cases, but for the controls, the selection is not described, although all the studies except one had defined the controls. All the studies except three fulfilled the comparability assessment. Most of the studies had fulfilled the exposure assessment. Altogether, seven studies had a score of more than 6*s, namely that of Kalantaridou et al, van der Stege et al, Gulhan et al, Doldi et al, Hartmann et al, Janse et al, and Ates et al. For sensitivity analysis of testosterone concentrations, the studies by Ates et al, Gulhan et al, and Doldi et al were not included because even though they scored 6*s on the scale, the selection methodology for cases and controls were not clearly mentioned. The studies by Kalantaridou et al, van der Stege et al, and Janse et al scored 7*s or more on the scale and were of the highest methodological quality. The study by Hartmann et al, while scoring only 6*s, had mentioned the selection methodology; it was just not clear if the participants were consecutively chosen, but because it mentioned how they were chosen as opposed to no description in the other three studies, it was included. Also the study by Doldi et al was included in the sensitivity analysis for androstenedione and DHEA-S because we wanted to compare a minimum of three studies to do the sensitivity analysis. The study by Doldi et al compared both androstenedione and DHEA-S, and scored more than 6*s on the Newcastle-Ottawa Scale. In the absence of other higher-quality studies for these two androgens (androstenedione, DHEA-S), we included this study in the sensitivity analysis. The study by Benetti-Pinto et al had no description of how cases and controls were selected. The study by Elias et al did not have age or BMI-matched cases and controls, nor did it have description of how cases and controls were selected. The study by Falsetti et al had no description of how cases and controls were selected, nor did it have description if both cases and controls used similar tests to check for exposure.

TABLE 5

TABLE 5

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RESULTS

Testosterone concentrations

Women suffering from POI/POF have lower testosterone in comparison to the controls according to data retrieved from 14 studies (n = 1,656) (Table 1), SMD (IV, random, 95% CI) −0.73 [−0.99, −0.46] with P value < 0.05 (Fig. 2). There was significant heterogeneity observed in the meta-analysis (I 2 = 82%). With heterogeneity: Tau2 = 0.19; χ2 = 72.18, df = 13 (P < 0.00001); so, random-effects model was used. The funnel plot was evaluated to check for publication bias. A subgroup analysis was done to verify the source of heterogeneity. The sensitively analysis showed a consistency among the studies.

FIG. 2

FIG. 2

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Subgroup analysis for total testosterone concentrations

The subgroups were divided according to the various assays used for measurement. For the analysis of total testosterone concentrations, there were four subgroups identified. The first subgroup consisted of four studies which directly applied radioimmunoassay (RIA) for the measurement of testosterone concentrations. The second subgroup consisted of five studies which used extraction or chromatography before applying RIA. The third subgroup consisted of four studies which utilized the chemiluminescent immunoassay. And the fourth subgroup consisted of only one study in which it was not clear which assay was used [see Fig., Supplemental Digital Content 2, http://links.lww.com/MENO/A334]

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Direct RIA subgroup

The subgroup consisted of four studies (n = 280). This subgroup showed an SMD of −1.13 [−1.44, −0.82] test for overall effect: Z = 7.23 (P < 0.00001) with substantial decrease in heterogeneity (Tau2 = 0.03; χ2 = 4.05, df = 3 [P = 0.26]; I 2 = 26%).

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Extraction/chromatography RIA subgroup

The second subgroup consisted of studies which used extraction or chromatography before applying RIA. This consisted of five studies (n = 859). This subgroup showed an SMD of −0.66 [−0.99, −0.34], Z = 4.00 (P < 0.0001). Heterogeneity was still substantial in this subgroup with Tau2 = 0.09; χ2 = 14.08, df = 4 (P = 0.007); I 2 = 72%. The source of this heterogeneity could be explained by the fact that three of the five studies included in this particular subgroup happened to be lower-quality studies and were not age or BMI-matched. We tried removing these three studies from this subgroup and saw that the heterogeneity had substantially reduced to about 4%.

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Chemiluminescent immunoassay subgroup

The subgroup consisted of studies measured using the chemiluminescent immunoassay, and it consisted of four studies (n = 455). This subgroup showed a SMD of −0.20 [−0.38, −0.01], Z = 2.10 (P = 0.04). This subgroup showed no heterogeneity with Tau2 = 0.00; χ2 = 1.30, df = 3 (P = 0.73); I 2 = 0%.

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Other/nonspecified assay subgroup

The subgroup consisted of only one study (n = 62). This subgroup showed an SMD of −1.88 [−2.48, −1.28], Z = 6.10 (P < 0.00001).

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POI/POF versus fertile controls versus postmenopausal controls

The POI/POF versus fertile controls subgroup showed a SMD (−0.73 [−0.99, −0.46]) with P value <0.05, whereas the POI/POF versus postmenopausal controls (n = 465) showed a SMD of −0.05 [−0.68, 0.58] test for overall effect: Z = 0.15 (P = 0.88). Heterogeneity: Tau2 = 0.27; χ2 = 14.92, df = 2 (P = 0.0006); I 2 = 87%. The test for subgroup differences: χ2 = 3.77, df = 1 (P = 0.05), I 2 = 73.5%, indicating substantial heterogeneity between these subgroups (see Fig., Supplemental Digital Content 3, http://links.lww.com/MENO/A335).

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Sensitivity analysis for testosterone concentrations

Sensitivity analysis was first conducted using the leave-one-out method by systematically omitting one study at a time, and the results were robust. Then, four studies (n = 615) that scored 6 or greater on the Newcastle-Ottawa Scale, considered as the best-quality studies, were chosen out of the 14 studies. Seven studies had a score of more than 6, namely the studies by Kalantaridou et al, van der Stege et al, Gulhan et al, Doldi et al, Hartmann et al, Janse et al, and Ates et al. The studies by Ates et al, Gulhan et al, and Doldi et al were not included, because even though they scored 6 on the scale, the selection methodology for cases and controls were not clearly mentioned. The studies by Kalantaridou et al, van der Stege et al, and Janse et al scored 7 or more on the scale and were of the highest methodological quality. The study by Hartmann et al, while scoring only 6, mentioned the selection methodology; it was just that it was not clear if the participants were consecutively chosen in this study, but because it mentioned how they were chosen as opposed to no description in the other three studies, it was included. These studies used for the sensitivity analysis were the ones with the best methodological quality and considered having the least amount of bias, and all these studies were age and BMI-matched; this showed an SMD of −0.74 [−0.92, −0.55], Z = 7.80 (P < 0.00001). With a drop in heterogeneity to 0%: Tau2 = 0.00; χ2 = 2.53, df = 3 (P = 0.47); I 2 = 0% (Fig. 3).

FIG. 3

FIG. 3

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Dehydroepiandrosterone sulfate concentrations

Women suffering from POI/POF have lower DHEA-S in comparison with the controls according to data retrieved from eight studies (n = 911) (Table 2) (SMD [IV, random, 95% CI] −0.65 [−0.92, −0.37]), with P value <0.05. There was significant heterogeneity observed in the meta-analysis (I 2 = 71%), with heterogeneity: Tau2 = 0.11; χ2 = 24.44, df = 7 (P = 0.0010); so, random-effects model was used. The funnel plot was evaluated to check for publication bias. A subgroup analysis was done to verify the source of heterogeneity. The sensitively analysis showed a consistency among the studies (Fig. 4).

FIG. 4

FIG. 4

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Subgroup analysis for DHEA-S concentrations

The subgroups were divided according to the various assays used for measurement. For analysis of DHEA-S concentrations, there were two subgroups identified. The first subgroup consisted of six studies which directly applied RIA for the measurement of DHEA-S concentrations. The second subgroup was the studies in which the assays used were either not mentioned or needed more clarification. This consisted of two studies (see Fig., Supplemental Digital Content 4, http://links.lww.com/MENO/A336).

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Direct RIA subgroup

The subgroup consisted of six studies (n = 398). This subgroup showed a SMD of −0.60 [−0.90, −0.29], Z = 3.79 (P = 0.0002) with a decrease in heterogeneity: Tau2 = 0.08; χ2 = 10.94, df = 5 (P = 0.05); I 2 = 54%. The source of this heterogeneity could be explained by the fact that three of the six studies included in this particular subgroup happened to be studies with lower methodological quality. The study by Benetti-Pinto et al had no description of how cases and controls were selected. The study by Elias et al did not have age or BMI-matched cases and controls, nor did it have a description of how cases and controls were selected. The study by Falsetti et al had no description of how cases and controls were selected, nor did it have a description if both cases and controls used similar tests to check for exposure. We tried removing these studies from this subgroup and saw that the heterogeneity had substantially reduced to about 0%.

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Other/nonspecified assay subgroup

The subgroup consisted of only two studies (n = 513). This subgroup showed a SMD of −0.74 [−1.35, −0.14], Z = 2.39 (P = 0.02), with very high heterogeneity: Tau2 = 0.17; χ2 = 10.32, df = 1 (P = 0.001); I 2 = 90%. Both studies included in this subgroup were of lower methodological quality, and both were not age and BMI-matched in selecting cases and controls.

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POF versus fertile controls versus postmenopausal controls (DHEA-S)

The POI/POF versus fertile controls subgroup showed a SMD (IV, random, 95% CI) −0.65 [−0.92, −0.37], with P value <0.05. POI/POF versus postmenopausal controls (n = 465) showed a SMD 1.12 [0.10, 2.14], Z = 2.15 (P = 0.03), heterogeneity: Tau2 = 0.77; χ2 = 35.54, df = 2 (P < 0.00001); I 2 = 94%, indicating that the DHEA-S levels are much reduced in POI/POF cases, but still show a higher concentration than DHEA-S in postmenopausal women. Test for subgroup differences showed χ2 = 10.46, df = 1 (P = 0.001), I 2 = 90.4%, indicating substantial heterogeneity between these subgroups (Fig. 5).

FIG. 5

FIG. 5

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Sensitivity analysis for DHEA-S concentrations

Sensitivity analysis was first conducted using the leave-one-out method by systematically omitting one study at a time, and the results were robust. Three studies (n = 210) that scored 6 or greater on the Newcastle-Ottawa Scale, considered as the best-quality studies, were chosen out of the eight studies, namely the studies by Doldi et al, Hartmann et al, and van der Stege et al. The study by van der Stege et al scored 7*s on the Newcastle-Ottawa Scale and was of the highest methodological quality. The studies by Doldi et al and Hartmann et al scored 6*s on the Newcastle-Ottawa Scale, even though the selection methodology for cases and controls was not clearly mentioned. The study by Doldi et al, was included here as we wanted to use at least three studies to conduct the sensitivity analysis and these three were the highest-quality studies comparing DHEA-S. These were the studies with the best methodological quality and considered having the least amount of bias; in all these studies cases, controls were age, and BMI-matched. This showed a SMD of −0.46 [−0.74, −0.17], Z = 3.16 (P = 0.002), with a drop in heterogeneity to 0%: heterogeneity: Tau2 = 0.00; χ2 = 1.43, df = 2 (P = 0.49); I 2 = 0% (Fig. 6).

FIG. 6

FIG. 6

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Androstenedione concentrations

Women suffering from POF have lower androstenedione in comparison with the controls according to data retrieved from 10 studies (n = 1,226) (Table 3), SMD (IV, random, 95% CI) −1.09 [−1.71, −0.48], with P value <0.05. There was significant heterogeneity observed in the meta-analysis (I 2 = 95%). With heterogeneity: Tau2 = 0.92; χ2 = 180.64, df = 9 (P < 0.00001); so, a random-effects model was used. The funnel plot was evaluated to check for publication bias. A subgroup analysis was done to verify the source of heterogeneity. The sensitively analysis showed a consistency among the studies (Fig. 7).

FIG. 7

FIG. 7

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Smubgroup analysis for androstenedione concentrations

The subgroups were divided according to the various assays used for measurement. The first subgroup consisted of six studies that directly applied RIA for the measurement of DHEA-S concentrations. The second subgroup was the studies in which the assays used were either not mentioned or needed more clarification. This consisted of four studies (Fig., Supplemental Digital Content5, http://links.lww.com/MENO/A337).

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Direct RIA subgroup

The subgroup consisted of six studies (n = 398). This subgroup showed a SMD of −1.10 [−1.61, −0.58], Z = 4.17 (P < 0.0001) with heterogeneity: Tau2 = 0.34; χ2 = 27.45, df = 5 (P < 0.0001); I 2 = 82%. The source of this heterogeneity could be explained by the fact that three of the six studies included in this particular subgroup happened to be studies with lower methodological quality. The study by Benetti-Pinto et al had no description of how cases and controls were selected; the study by Elias et al did not have age or BMI-matched cases and controls, nor did it have a description of how cases and controls were selected; and the study by Falsetti et al had no description of how cases and controls were selected, nor did it have a description whether both cases and controls used similar tests to check for exposure. We tried removing these studies from this subgroup and saw that the heterogeneity had substantially reduced to about 2%.

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Other/nonspecified assay subgroup

The subgroup consisted of only four studies (n = 828). This subgroup showed a SMD of −1.08 [−2.30, 0.15], Z = 1.73 (P = 0.08) with very high heterogeneity: Tau2 = 1.52; χ2 = 150.25, df = 3 (P < 0.00001); I 2 = 98%. Two studies included in this subgroup were of lower methodological quality, and both were not age and BMI-matched in selecting cases and controls, namely the studies by Szlendak-Sauer et al and Daan et al; we tried removing these studies from this subgroup and saw that the heterogeneity had substantially reduced to about 5%.

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POF versus fertile controls versus postmenopausal controls (androstenedione)

The POI/POF versus fertile controls subgroup showed a SMD (IV, random, 95% CI) −1.09 [−1.71, −0.48] with P value <0.05. POI/POF versus postmenopausal controls (n = 466) showed a SMD 0.27 [−0.13, 0.67], Z = 1.34 (P = 0.18), heterogeneity: Tau2 = 0.08; χ2 = 5.97, df = 2 (P = 0.05); I 2 = 66%. Test for subgroup differences showed χ2 = 13.41, df = 1 (P = 0.0003), I 2 = 92.5% (Fig., Supplemental Digital Content 6, http://links.lww.com/MENO/A338).

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Sensitivity analysis for androstenedione concentrations

Sensitivity analysis was first conducted using the leave-one-out method by systematically omitting one study at a time, and the results were robust. Then four studies (n = 463) that scored 6 or greater on the Newcastle-Ottawa Scale, considered as the best-quality studies, were chosen out of the 10 studies, namely the studies by Doldi et al, Hartmann et al, van der Stege et al, and Janse et al. The studies by van der Stege et al and Janse et al scored 7*s on the Newcastle-Ottawa Scale and were of the highest methodological quality. The studies by Doldi et al and Hartmann et al scored 6*s on the Newcastle-Ottawa Scale. This showed a SMD of −0.82 [−1.16, −0.47], Z = 4.66 (P < 0.00001), with a drop in heterogeneity to 55%: heterogeneity: Tau2 = 0.07; χ2 = 6.65, df = 3 (P = 0.08); I 2 = 55% (Fig. 8).

FIG. 8

FIG. 8

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Sex hormone-binding globulin concentrations

Women suffering from POI/POF did not seem to have a statistically significant difference to fertile controls with regards to SHBG levels according to data retrieved from nine studies (n = 1,613) (Table 4); SMD (IV, random, 95% CI) −0.13 [−0.35, 0.09] with P value >0.05 (not significant) (see Fig., Supplemental Digital Content 7, http://links.lww.com/MENO/A339).

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DISCUSSION

In this systematic review and meta-analysis, we analyzed the various androgen concentrations including both the principal ovarian and adrenal androgens such as serum concentrations of total T, A, DHEA-S, and SHBG, and compared them with fertile controls and postmenopausal controls.

The pooled testosterone concentrations were found to be lower in women with POI/POF compared with fertile controls; SMD (IV, random, 95% CI) −0.73 [−0.99, −0.46] with P value <0.05. Testosterone concentrations in POI/POF versus postmenopausal controls were not statistically significant, with a SMD −0.05 [−0.68, 0.58], P value >0.05.

The pooled DHEA-S concentrations were found to be lower in women with POI/POF compared with fertile controls; SMD (IV, random, 95% CI) −0.65 [−0.92, −0.37] with P value <0.05. DHEA-S concentrations in POI/POF versus postmenopausal controls were statistically significant with a SMD 1.12 [0.10, 2.14], P value < 0.05, indicating that the DHEA-S levels are reduced in POI/POF, but still show a higher concentration than DHEA-S in postmenopausal controls. Women in the postmenopausal group are older than POI/POF women. It was only for DHEA-S that a significant decrease was noted in the postmenopausal group when comparing testosterone, DHEA-S, and androstenedione between POI/POF women and the postmenopausal group. The reasons for a significant decrease of DHEA-S seen in the postmenopausal group could be due to aging. The study by Labrie et al44 has summarized that DHEA secretion will have already decreased by an average of 60% at time of menopause and will continue to decrease thereafter. We propose that this difference in decreasing pattern in serum DHEA-S with increasing age between POI/POF women and the postmenopausal group is mainly due to a higher compensatory mechanism in the relatively younger POI/POF women. In women of all ages, the inactive sex steroid precursor DHEA is mainly of adrenal origin. The study by Labrie et al45,46 reported that the ovary is responsible for production of only 20% of circulating DHEA. The inactive DHEA will be transformed into the appropriate minute intracellular amounts of androgens to exert their physiological function. There is no biologically significant release into the serum for these intracellular androgens. This intracrine mechanism of androgen formation from DHEA could be responsible for why only for DHEA-S that a significant decrease was noted in the postmenopausal group, and why no significant difference was seen when comparing testosterone and androstenedione between POI/POF women and the postmenopausal group.

The pooled A concentrations were found to be lower in women with POI/POF compared with fertile controls; SMD (IV, random, 95% CI) −1.09 [−1.71, −0.48] with P value <0.05. Androstenedione (A) concentrations in POI/POF versus postmenopausal controls were again not statistically significant, with a SMD 0.27 [−0.13, 0.67], P value >0.05.

Women suffering from POI/POF did not seem to have a statistically significant difference compared to fertile controls with regards to SHBG levels according to data retrieved; SMD (IV, random, 95% CI) −0.13 [−0.35, 0.09], with P value >0.05.

There was significant heterogeneity between studies. Each of these androgens decreases with age. Most of the studies chosen had age-matched cases and controls, and only three studies did not match for age or BMI. So, we conducted a sensitivity analysis using only the best quality studies for each androgen assessed. In these studies, cases and controls were age and BMI-matched, and results showed substantial decrease in heterogeneity. Age and BMI were important factors in quality assessment for these studies involved. Some studies did not adjust for these factors. This could be one of the reasons for the heterogeneity between these studies. Another reason for heterogeneity between studies could be due to the differences in selecting controls and methodologies used for recruitment. Finally, the most important factor contributing towards the heterogeneity between studies could be explained by the fact that the studies used different assays for the measurement of androgen concentrations. This was apparently evident in the subgroup analysis using different assays (see Fig., Supplemental Digital Content3, 4, and 5, http://links.lww.com/MENO/A335, http://links.lww.com/MENO/A336, http://links.lww.com/MENO/A337). There was a substantial decrease in heterogeneity within most subgroups, which conducted analysis using the same assay. Few of the subgroups undertaken using the same assay showed reduced but still a significant level of heterogeneity. This could be explained by the fact that even though they were using the same kind of assay for measuring the concentrations, the intra and interassay coefficients used were widely variable. And, also, the source of this heterogeneity could be explained by the fact that few of these studies included happened to be lower-quality studies and were not age or BMI-matched or had no description of how cases and controls were chosen or if the same tests were used to ascertain exposure in cases and controls. The study by Benetti-Pinto et al21 had no description of how cases and controls were selected. The study by Elias et al7 did not have information on age or BMI for cases and controls, nor did it have a description of how cases and controls were selected. The study by Falsetti et al38 had no description of how cases and controls were selected, nor did it have description whether both cases and controls used similar tests to check for exposure. The studies by Szlendak-Sauer et al39 and Daan et al43 were not age and BMI-matched in selecting cases and controls. When these studies with lower methodological quality were removed from the respective subgroups, the heterogeneity substantially reduced. So we conducted a sensitivity analysis using only studies with the best methodological quality, in which the most important confounding factors were age and BMI, and we observed significant results and substantial reduction in heterogeneity in all of the androgens assessed.

Taking all these factors contributing to heterogeneity into account, SMD was used to estimate the pooled concentrations and a random-effects model was used. SMD was preferred over a mean difference, because the methodologies used for estimation of the concentrations widely varied and this variation is already acknowledged by using SMD for estimation. Also, the sensitivity analysis using the best quality studies proved that the results obtained were robust. Therefore, we may interpret the results of this meta-analysis as being statistically significant.

The major androgens found in women in descending order of their serum concentrations include the following: DHEA-S, A, and T.47 Of these androgens, T is the most potent.48 It is secreted by the adrenal zonafasciculata (25%) and the ovarian stroma (25%), with the remaining 50% being produced from circulating A.49 DHEA is a secretory product of the adrenal zonareticularis (50%) and the ovarian theca (20%), and 30% is derived from circulating DHEA-S, catalyzed by steroid sulphatase.49 Androstenedione is secreted by the adrenal zonafasciculata (50%) and the ovarian stroma (50%).49 We have identified decreased concentrations of these androgens, namely DHEA, which is produced mostly by the adrenal glands; however, it is still not clear whether this reduction is solely due to the ovarian component or if the adrenal component is also affected in idiopathic POI/POF.

The consequences of androgen deficiency have been discussed in very few studies. Androgens are thought to be one of the basic prerequisites for a healthy woman.7-14 A lack of androgens may lead to symptoms of sexual dysfunction, such as decreased libido, loss of sexual responsiveness, or decreased sexual arousal.7-14 Other clinical symptoms are a diminished sense of well-being, dysphoric mood, cognitive dysfunction, and persistent, unexplained loss of energy.7-14

The role of androgens in maintaining a woman's health has been receiving increasing attention, but still, there is considerable controversy relating to the role of androgens in women, and its clinical significance.4,13-21 Testosterone at supraphysiological, but not at physiological, levels enhance the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supraphysiological testosterone increases women's sexual desire in combination with an estrogen remains unknown.12 Clinical evidence suggests that testosterone has anxiolytic and antidepressant benefits, with the potential to promote improved mood and mental health in women.50 However, the neurobiological mechanisms underlying the protective effects of testosterone in males and females remain poorly understood. Selective androgens appear capable of improving early stages of folliculogenesis. Androgens, like T, appear effective in improving functional ovarian reserve in women with diminished ovarian reserve.51 A study found that a low-testosterone status is a potentially important step in the development of POI/POF in women with endometriosis.52 In women with diminished ovarian reserve, the basal T level presented a positive association with pregnancy outcome in in vitro fertilization.52

This meta-analysis has a few limitations. Very few studies were available for the topic of interest that would meet the eligibility criteria. Inclusion criteria were somewhat limited in databases assessed, some studies with lower methodological quality were included; this lead to significant heterogeneity between the studies. We have rectified these issues of including lower methodological quality studies by conducting a sensitivity analysis with higher methodological quality studies only. Each of these androgens decrease with age, most of the studies chosen had age-matched cases and controls. Only three studies did not match for age or BMI. Again, we conducted a sensitivity analysis using the best quality studies for each androgen assessed, in these studies cases and controls were age and BMI-matched; and the results seemed to be consistent and robust. Further, it is very difficult to measure and compare these sex steroids at lower ranges with accuracy using various assays. This was another challenge we faced while conducting this meta-analysis. Based on this limitation in assessment, we had to standardize the units of measurement and use a SMD and random-effects model to account for these differences. Currently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a widely accepted and accurate assay for measuring low levels of steroids, such as androgens. Further comparative studies which employ LC-MS /MS, or similar assays, are needed to make sure the results obtained using various other assays can be depended upon.

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Potential clinical value

Our meta-analysis has found that there is significant androgen deficiency in women with POI/POF. A significant reduction in androgen levels could lead to various complaints. Using androgen replacement therapy as an adjunct to pre-existing estrogen-based replacement therapy could be advantageous in relieving health complaints and promoting a more qualitative life in these women. Also, we suggest that, because the assays used for measurement of various androgens are widely variable, a standardized method for measurement needs to be developed for accurate assessment of these indices.

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CONCLUSIONS

In conclusion, this meta-analysis demonstrated that women with POI/POF are at risk for decreased concentrations of total testosterone, DHEA-S, and androstenedione. SHBG concentrations did not show any statistical significance between POI/POF and controls. DHEA-S levels were more reduced in postmenopausal controls when compared with POI/POF cases. Testosterone and androstenedione concentrations did not show any statistical significance when POI/POF cases were compared with postmenopausal controls.

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Keywords:

Androgen; Androstenedione; DHEA-S; Premature ovarian insufficiency; SHBG; Testosterone

Supplemental Digital Content

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© 2019 by The North American Menopause Society.