Dramatic acceleration of reproductive aging, contraction of biochemical fecundity and healthspan-lifespan implications of opioid-induced endocrinopathy—FSH/LH ratio and other interrelationships
Highlights
· The classically described opioid related female reproductive endocrinopathy including central dysregulation and peripheral ovarian resistance is confirmed.
· Advance of the age of the inversion of the ratio of FSH/LH by 18.06 years from 46.26+4.76 to 28.06+9.36 is demonstrated by statistical modelling
· This important finding is likely related to the sexual differential in opioid pathophysiology in which females are significantly disadvantaged.
· Statistical modelling showed that many elements of the reproductive endocrinopathy had a non-linear relationship to chronological age, including squared, cubed and quartic functions of age suggesting a feed-forward bidirectional relationship with age and the ageing process.
· These findings have major implications for the incidence of morbidity and mortality events, and for frequently recommended treatments such as indefinite opioid agonist replacement therapies for opioid dependence.
Abstract
Whilst disturbances of female reproductive hormones and function are commonplace in opioid dependence, their pathophysiological interrelationships are not well understood. Hormonal levels in females were compared in 77 opioid dependent patients (ODP) and 148 medical controls (MC) including 205 and 364 repeat studies. Significant changes in FSH, LH, oestradiol, testosterone and SBG were noted including power functions with age.
The FSH/LH was lower in ODP (P=0.0150) and the ratio inversion point occurred at 28.06+9.36 v. 46.26+4.76 years, implying a 58% reduction in fertility duration. FSH has been shown to induce ovarian failure and GnRH (controlling LH and FSH) has been shown to regulate longevity systemically. This implies that, far from being benign, these findings explicate the adverse experience of female compared to male ODP, exacerbate opioid-dependent aging amongst females, and informs the care of opioid dependent women, particularly relating to the choice, dose and duration of agonist or antagonist therapy.
Introduction
Rates of morbidity and mortality from medical and illicit opioid dependence are rising in manyparts of the world, with the proportion of female consumers increasing [1-3].
Accordingly, increasing attention is not only being paid to the effects of chronic opiate exposure on traditional areas of women’s health such as pregnancy, lactation and contraception, but also domestic violence, child abuse, manner of initiation into opiate use, time to from first use to dependence and physical and mental health morbidity [4-9].
Reports from this centre [10] and elsewhere [11, 12] indicate that the health of opioid dependent women is significantly worse than that of non-opiate using women or their male counterparts.
It has been shown that the hypothalamopituitary-gonadal (HPG) axis is coordinated and integrated particularly by the triple positive Kisspeptin-Neurokinin B-Dynorphin (KNDy) cells of the lateral hypothalamus [13, 14]; that cytokines have a powerful impact on brain structure and function [15, 16]; and HPG and hypothalamic function [17]; that the hypothalamus integrates and controls mammalian lifespan via gonadotrophin releasing hormone (GnRH) [18]; and that sexual reproductive and fecundity factors are powerful predictors of longevity [19, 20].
This suggests that disruption of these integrated systems through opiate use would have a profound pathophysiological impact that extends beyond gynaecological, endocrine or addiction medicine. While different gender associated health outcomes are, in part, attributed to different sex hormones or ratios, more recent data of profound genetic [21], immunological [21-25] and epigenetic [26] gender differences imply that the total aetiological “palette” of factors with which the hormonal milieu bi-directionally interacts may be significantly richer and more complex than has previously been appreciated.
Reduced fertility, impaired lactation, and aberrant, late and scanty menses are all well described in the literature relating to female opioid dependent patients [27-29]. Premature ovarian failure may also be part of the picture. Osteoporosis and osteopaenia are also known to be common in male and female opioid dependent patients (30,31), and impaired bone homeostasis is known to be related to both hypogonadal and hypothalamic failure and immune stimulation (24,29).
Of particular interest hypothalamic GnRH [18] and FSH [30] have recently been causally implicated in reduced mammalian lifespan, and oocyte depletion and ovarian failure respectively. The hypothalamic GnRH pulse generator in the arcuate nucleus is known to be the master regulator of both commencement of menstrual cycles at menarche and the cyclicity of the cycles once established [31, 32]. Age at menarche is linked with lifespan, cardiovascular disorders, type 2 diabetes and breast cancer [31]. Its activity is governed by nuclear hormone (estrogen, progesterone, thyroid hormone and vitamin D) signalling, by many genes of the δ- aminobutyric acid B receptor (GABABR) 2 system, by nutritional signals including the leptin receptor, histone and polycomb silencing complex demethylation patterns and steroidal biogenesis pathways amongst others [31]. Opioids have been shown to be directly suppressive of GnRH release both directly [33] and via their effects in elevating prolactin [27, 28].
Indeed the proopiomelanocortin cells of the arcuate nucleus are physiological negative regulators of the GnRH pacemaker cells [33]. Moreover a direct effect of oestradiol on telomerase expression in human stem cells has been demonstrated [34]. Hence multiple interacting mechanistic pathways exist by which opioids can interact with nutritional and metabolicfunction and reproductive hormonal status.
Thus while it has long been recognized that systemic health factors impact upon a woman’s reproductive fitness, these considerations imply that HPG physiology may itself be a sensitive – if complex – readout of the female hypothalamic function. Female HPG factors may integrate and provide an output of systemic health, and thereby formulate a prospective predictor of longevity and thus health-based morbidity and mortality [18, 35, 36].
For these reasons this study reviewed and compared female reproductive hormones of opioid dependent and general medical controls with particular attention to FSH, LH and their relationship. Other key ratios of physiological significance are also described.
Methods
Patient Selection As hepatitis C serology is only performed in this clinic on drug dependent patients this test is a surrogate marker for the drug dependent state. Patients were therefore assigned to either the medical control group or the drug dependent group based upon whether or not they had had hepatitis C serology performed.
The analysis included results from all patients for whom pathology was requested. Two patients who were pregnant were excluded from the analysis. The age range was restricted to 15-50 years in view of the dramatic changes in the hormonal milieu in females in the reproductive age group compared to other periods ofa woman’s life. This is also the period in which the majority of addiction occurs. Blood tests were taken in the period 1995-2015 as clinically indicated for patient care in the course of their routine medical care.
Pathology Analysis.
All pathology was performed by Queensland Medical Laboratory (QML) according to National Association of Testing Authorities Australia (NATA) accredited methods to the Australian Laboratory standard AS-15189. QML is accredited both with NATA and to the international clinical laboratory standard ISO 9001. The Free Androgen Index (FAI) was obtained from the laboratory and is defined as 100x Total Testosterone / Sex Hormone Binding Globulin (SBG). The Free Estradiol Index (FEI) was defined similarly as 100x Total Estradiol / Sex Hormone Binding Globulin [37]. Other ratios which were specifically defined and studied include the FSH/LH, LH/Testosterone, LH/Estradiol and FSH/ Progesterone indices.
Statistics.
Pathology data was downloaded as an Excel comma separated file (csv file) from QML and re-formatted as a Microsoft Excel worksheet. Categorical data were compared in EpiInfo 7.1.4.0 from Centres for Disease control in Atlanta Georgia, USA. Bivariate statistics were compared by categories in Statistica 7.1 from Statsoft, Oklahoma, USA. All t-tests were two tailed. “R” version 3.0.1 was downloaded from the University of Melbourne Central “R” Archive Network (CRAN) mirror. Continuous data was compared in “R”. Continuous data was log transformed to satisfy normality assumptions, as indicated by the Shapiro test. Linear regression was performed in “R”. Graphs were drawn using ggplot2 in “R”. Loess curves of best fit were drawn as localized polynomials. Linear regression was performed by the classicalmethod with deletion of the least significant term until only significant terms remained.
In view of the fluctuating levels of sex hormones across the lifespan, polynomial models in age were fitted as suggested by the form of the graphical loess curves. Final models for analysis were chosen based on an Analysis of Variance (Anova) comparison of final polynomial models for each dependent variable, as indicated in the text. Special interest centred on the log (FSH/LH) ratio. As explained in the text the points at which it crossed zero in each group were of particular interest. These points were estimated based on Fieller’s theorem, as were the associated confidence intervals. P<0.05 was considered significant.
Ethics. Ethical approval for this study was given by the Human Research Ethics Committee (HREC) of the Southcity Medical Centre (SMC). The SMC HREC has been accredited by the National Health and Medical Research Centre (NHMRC). The conduct of this study complied with the Declaration of Helsinki.
Results
753 opioid dependent patients (ODP’s) and 1867 medical control (MC) patients were compared. All patients were in the age range 15-50 years. The mean ages in the two groups were 31.42+0.27 (mean+SEM) and 30.34+0.22 years respectively (Student’s t = 2.96,df =1727, P = 0.0020). Their clinical pathology was sampled on 1360 and 4310 occasions. All patients were female. In seven cases their group assignment changed based on their drug use dependency status which changed over the course of the study.
Since this data is derived from our clinical pathology no other demographic or drug use data is available. Drug use and demographic data for this cohort has previously been presented [38- 41]. Similarly no menstrual or contraceptive data is available. Table 1 shows a bivariate comparison of the two groups. The data presented relates only to the first occasion on which each patient was studied. The data are presented by category.
Significant differences are noted between the two groups on metabolic, hepatic, immune and infectious parameters, and on the two hormonal parameters oestradiol and the sex hormone binding globulin SBG. SBG is produced from the liver and is not usually classified as a hormone, but many aspects of its function resemble hormonal activity since its level and binding characteristics and subtypes determine the hormonal availability particularly of oestradiol and testosterone to the tissues. It’s level is known to rise in hepatic dysfunction [42,43]. It is therefore considered as a hormone for the purposes of this analysis. This table also
presents the sample sizes of the different groups on the first occasion they were analyzed and
in the cross-sectional dataset. As opioids are known to impact metabolic, immune and hepatic
function [44, 45] these various parameters are reported and show many significant differences.
The sample size in the longitudinal dataset is shown in Supplementary Table 1.
Figure 1 presents the hormonal levels by age. The rise of the gonadotrophins LH and FSH, the decline of the sex hormones oestradiol, progesterone and testosterone with age, is well known. SBG is also noted to fall with age. It is noted that all the figures show the changes up to age 60 years, whilst the statistical analysis is limited to changes occurring less than age 50 years.
This allows the changes in the data trend lines to be shown graphically, but allows the analysis to be conducted without the confounding effect of the dramatic hormonal changes which occur in females as they enter their sixth decade of life. Supplementary Figure 1 shows the same hormones over time. Figure 2 shows various selected hormone ratios as a function of chronologic age. Interestingly the FAI and FEI both appear lower throughout life, apparently due to the higher SBG noted in Figure 1.
The relationship of LH/estradiol, FSH/Progesterone and LH/testosterone, which are all
physiologically meaningful, is shown. Supplementary Figure 2 shows these ratio relationships over time.
Figure 3 displays the mean log ratios between the hormones and ratios in the opioid dependent group to that in the opioid naive group. The figure shows that SBG is elevated the most, and LH is depressed the most severely in ODP. Similarly the FSH/LH ratio is most elevated whilst the LH/Estradiol ratio is most depressed. The presentation in this manner allows the direct and rapid comparison of the various changes across the spectrum of parameters examined.
Table 2 summarizes the results from mixed effects repeated measures linear regressions in which terms for the addictive status were significant. The first column lists the biological parameter of interest. The second column gives the form of the model. The third column gives the statistical parameter measured. The remainder of the table lists the parameter and model values respectively. One notes that progesterone, LH/estradiol and LH/Testosterone are missing from the table, as the optimal model for these contained no significant term in addictive status. One will note that the higher order design of the optimal model chosen in this table closely parallels the form of the curves in Figures 1and 2. This Table emphasizes the polynomial relationship of these hormonal parameters with age.
Table 3 is a statistical technical table which formally presents a concise extract from Anova analyses of model comparisons which lead to the choice of model design in Table 2. Naturally it would have been too cumbersome to present all the model comparisons, so typically the linear model is compared with the best or next best model determined by Anova. This Table emphasizes that models polynomial in age account for the variance in the data very significantly better than simple linear models.
The serum prolactin levels were not different between the two groups considered either by chronological age or by time (data not shown). Interestingly the FSH and LH appear to have a very different relationship, even when plotted as logarithms in Figure 1. This is of particular interest, as the FSH is normally lower than the LH in the reproductive years, but the relationship reverses premenopausally and in the postmenopause. This crossover point is therefore of particular biochemical and endocrinologic interest. We then returned to the fascinating subject of the point at which the log(FSH/LH) ratio became equal to zero in Figure 1. Clearly a log(FSH/LH) = 0 has a similar physiological meaning to FSH/LH = 1. It was possible to estimate this point using Fieller’s theorem.
The estimates given for the ODP was 28.06+9.36 years, and for the medical controls 46.26+4.76 years. Clearly this is a truncation of this measure of the perimenopause by 18.20 years. If one assumes a menarche occurring at 15 years [46], this represents a compression of this measure of hormonal fertility from 31.26 years in MC patients to 13.06 years in ODP, a 58.2% reduction.
Since liver disease is known to elevate both estrogen and SBG it may be considered that the high rates of liver disease in this population were significant confounding effects for the primary comparison described in this study. Importantly hepatitic inflammation is known to elevate both estradiol and SBG [27, 32] so that these hepatofugal effects on their relative relationship, and thus their effect on the free circulating estrogen is uncertain. These confounding factors were therefore evaluated formally. By comparing controls with opioid dependent patients who were both infected and uninfected with hepatotrophic viridae the effect of drug dependency alone can be isolated from a concomitant effect of hepatic inflammation.
Supplementary Figures 3-5 show the effect of seropositivity for HbsAg (Hepatitis B surface antigen) , HBcAb (Hepatitis B core antibody) and HCV (Hepatitis C virus) on the estradiol, SBG, Free Estrogen Index (FEI) FSH, LH and FSH/LH ratio respectively. Patients were considered to be hepatitis C positive if the HCV PCR (Polymerase chain reaction) was positive or the HCV antibody was positive in the absence of a negative HCV PCR result. These results are shown in the Supplementary Figures. Three groups were considered – non hepatitic control patients, patients tested and found to be negative, and patients tested and found to be positive.
Formal statistical analysis of these data by selected hormonal parameters in mixed effects repeated measures models are shown in Supplementary Tables 2-4. In each case the medical control patients were used as statistical comparator controls for linear regression modeling which was undertaken in R. Only statistically significant results are listed in the Tables.
Figure 4 illustrates the effect of Hepatitis B or C seropositivity considered together on these hormones and their ratios, and Table 4 provides the applicable statistical analysis for log (FSH/LH) compared to the medical control group. These studies show that in uninfected opioid dependent patients estradiol is mildly elevated at trend level significance (P=0.08-0.09) except in the case of HBcAb where this elevation reaches significance (P=0.0135, Supplementary Table 2). Estradiol is further elevated by chronic viral hepatitis (all P<0.02). Our analysis shows that opioid dependency alone without chronic viral hepatitis (CVH) significantly elevates SBG (most P≤0.01), an elevation which is furthered by CVH (P≤0.001, Supplementary Table 3). However when these two indices are considered together as the (log) Free Estrogen Index these effects are mostly abrogated
(Supplementary Table 4).
Opioid dependency elevates the FSH and reduces LH so that the net effect of opioid dependency on the (log) FSH/LH ratio is to raise it in both CVH -infected and -uninfected opioid dependent patients. As shown graphically in the Figures and quantitated in Table 4, theeffect is actually more marked in uninfected ODP (most P≤0.002) in the case of Hepatitis B,and is highly statistically significant in both HCV -infected and -uninfected ODP patients.
Another way in which to compare the relationship between hepavirus infection and drug dependency status directly from our data is to include both factors as independent variables in models of our main parameter of interest. In such models the classical regression process of model reduction from initial to final model should either completely remove extraneous variables, or indicate their relative weights. Unsurprisingly this was not possible when addictive status and Hepatitis C status was considered concurrently, or when all hepaviridae were considered together with addictive status, as all such models both linear and quadratic for age failed to converge due to collinearity. However it was possible to compare HBsAg and addictive status together with age directly in mixed effects models of Estradiol, SBG, FEI and log (FSH/LH). Whilst models linear in age were functional in this analysis higher order models as suggested by Table 3 in general failed to converge (other than as shown in Supplementary Table 5). Detailed results for linear mixed effects models are presented in Supplementary Table 5 which shows that opioid dependency features in five terms in this table and HBsAg status is included in four terms with effect sizes broadly comparable. This result indicates that both addictive status and Hepatitis B virus infection together are statistically significant determinants of these parameters.
When models accounting for the variance of the log (FSH/LH) ratio were formally directly compared by Anova comparisons of mixed effects maximum likelihood models the addictive status was more highly predictive than the HbsAg serostatus. The addition of addictive status to age as dependent variables was more significant than the addition of HBsAg to age (AIC’s 1257.84 v 1274.49. Log Ratio = 14.65, P = 0.0001) and the addition of a term for HbsAg status did not significantly improve an additive model between age and addictive status (AIC’s 1259.22 v 1257.84, Log Ratio = 2.61, P=0.2703).
Overall these data show that whilst both HBV and HCV CVH elevate both estradiol and SBG,their rise is proportional so that when considered as the Free Estrogen Index there is little change seen in opioid dependence. This result implies that the biologically available level of oestradiol is unchanged by hepaviridae infection. However when one considers the gonadotrophins both CVH -infected and -uninfected opioid dependent patients display elevated FSH, depressed LH and therefore a markedly and highly significantly elevated FSH/LH ratio which is therefore independent of the CVH status. These data indicate therefore that particularly in the case of the gonadotrophins, the observed changes relate more to the opioid dependency than the chronic viral hepatitis infection as confirmed in the analysis of log(FSH/LH) when both addictive and infective independent variables are included as factors concurrently.
Discussion
These data confirm and extend previous data showing perturbation of reproductive hormonal axes in opioid dependence amongst females. Data indicate that opioid dependence is characterized by marked fluctuation from normal in the mean levels of several sex hormones and their key physiological ratios from 50% elevated to 50% reduced. A key factor in this is the increased SBG level which rises presumably due to hepatic stimulation which is known to occur in ODP related to cytokine stimulation and often infection with hepatotrophic viridae including Hepatitis B and C [42, 43]. Significant alterations in FSH, LH, estradiol, testosterone and SBG, and in the FAI, FEI, FSH/LH, LH/estradiol, and FSH/Progesterone ratio were demonstrated in sensitive models, mostly polynomial in chronological age.
Particularly interesting findings relate to the altered FSH/LH ratio.
Early in a young woman’s life the FSH is low and the LH generally higher. After the menopause the reverse situation applies, so that the crossover or equality point becomes a sensitive biochemical and endocrinologic marker of the premenopause. Because FSH has been shown to have an aetiological role in ovarian failure and therefore the decline in systemic health [30], this is a very important biochemical harbinger of systemic health and likely foreshadows healthspan.
Study data indicate the FSH/LH equality point for opioid dependent women is reached at 28.06+9.36 years as opposed to 46.26+4.76 in controls. This likely represents a severe reduction in this measure of the reproductive lifespan and optimal reproductive fitness from 31.26 years to 13.06 years (58.2% ). This in turn implies an increased incidence of premature ovarian failure in opioid dependence. None of these findings were simply explainable on the basis of co-existing hepatitic liver disease alone.
Earlier studies showing that altered gonadotrophin levels have a systemic effects contributing to longevity [18] and in particular the role of FSH in contributing causally to ovarian compromise [30], together with the well described impact of fertility and fecundity on lifespan and longevity [19, 20] implies in turn that the clearly demonstrated failure of physical health across all body systems [11] may in fact be related to systemically impaired health and indeed reduced healthspan. Healthspan is a term which refers to the period of life for which individuals maintain optimal health [47, 48].
Hence this dramatic alteration of reproductive fitness is likely to impact both the healthspan of women, and their lifespan or longevity as the rate of aging is known to accelerate dramatically after both the menopause and in the fifth decade (after the age of forty) when the FSH/LH ratio normally inverts. This is turn carries major implications for the type and duration of treatment for the illicit opiate user. For example whilst internationally most opioid dependent patients are maintained on methadone, an opioid agonist or buprenorphine, a partial agonist, however it may be that maintenance on an opioid antagonists such as naltrexone or nalmefene may re-awaken and reignite the HPG axis following extended chronic illicit opiate use [27, 28, 32, 49] and thereby repair and renovate the healthspan. Similarly most opiate agonist or partial agonist treatment regimes are usually recommended to be of indefinite duration. The principal aim of such treatment appears to be to minimize reduce crime and illicit opiate use, overdose related death, and spread of blood borne viral infection (i.e. HCV; HIV). However it would appear from exhaustive analyses [11] that such treatment comes at an inexorable cost of pan-systemic disease, potentially relating to allostasis in multiple systems [50, 51] and generalized derangement of health including dysmetabolism [52] and immune stimulation [35, 53] and ultimately immune exhaustion [54, 55].
It is of some interest that the OPD in this study have been shown elsewhere to be maintained upon a relatively low dose of buprenorphine with a mean of 6.98mg [10]. It is likely therefore that in cohorts managed more traditionally with high dose full agonists, these effects may be more profound. This heightens the concerns expressed at other points herein. The hormonal ratios chosen in this study were of physiological import, as LH controls estradiol and testosterone secretion, and FSH is a prime determinant of progesterone secretion. The importance of the FAI and the FEI relate to the free availability of physiologically active levels of androgen and estrogen respectively. The importance of the FSH/LH ratio as a sensitive endocrinological measure of the premenopause has been mentioned above.
Of particular concern is the repeated demonstration that the effects of opioid dependence may be more severe in female patients [10-12]. The present clear demonstration of the altered female hormonal milieu of opioid dependence implies that endocrine factors may be an important, if likely not the only factor in this heightened disease severity. Whilst this finding is clearly suggestive it cannot be regarded as demonstrating a necessarily causal relationship between hormonal dysregulation and heightened female sensitivity to opioid induced pathophysiology. Although this study did not show any differences in either the time- or age- dependent changes in serum prolactin levels by group, it is well established that long term opioid administration is associated with hyperprolactinaemia [27, 28, 32, 49]. Greying of the temporal hair is well known to be the sine qua non of human aging [56] and this key metric has previously been shown to be greatly advanced in opioid dependency [39].
It is fascinating therefore that both the cellular stress system mediated in all addictions by Activator Protein-1 (AP-1) and c-Jun terminal kinase (JNK) activity [57], together with the prolactin receptor (prlr) were recently demonstrated to be the most salient signalling transduction pathways of extrinsic pro-ageing signals to the stem cells of the hair bulge where they were integrated with cell-intrinsic epigenetic processes particularly Foxc1 status to regulate hair follicle stem cell aging and thus hair physiological status [58], which are clearly therefore important and powerful metrics of ageing in accelerated aging syndromes such as opioid dependency. Of particular interest is the clear demonstration in Tables 2 and 3 that many of these hormones and ratios are best modelled by non-linear functions polynomial in chronological age. This is a very important finding as it suggests not only that opioids effect hormonal function in a deleterious manner, but that a feed forward relationship is in operation. That is that opioids effect the hormonal status negatively, but this advance in biological-hormonal age then further exacerbates the reproductive ageing effects themselves. This is consistent with the effects of sexuality and fecundity on the ageing process itself as has been previously documented [19, 56].
The present study has a number of strengths and limitations. It is of significant size, and has both cross-sectional and longitudinal components. It uses advanced statistical polynomial repeated measures mixed effects modelling in conjunction with graphical and Anova model comparison analyses. Whilst the study is descriptive only and not mechanistically oriented, this observational framework is placed within a relatively sophisticated pathophysiological conceptual framework as a stimulus and springboard to future work. The shortcomings of this study include that it does not have drug use data included in it, and that hormonal and contraceptive details are not available. All of these features may be improved in future iterations or replications of this work. It is also noted that the mean ages of the two groups is significantly different. Extensive use of linear regression techniques has been made in the analysis of this dataset to account for this.
In conclusion this observational study replicates and confirms previously noted reproductive endocrinopathies. However while earlier authors frequently discount the clinical significance of these findings it is likely that they contribute meaningfully both to the experience of females in opioid dependence, and also the heightened morbidity and organ specific mortality frequently experienced by OPD women. The dramatic reduction of the modelled FSH – LH age of equality from 46.26 to 28.06 years is of particular concern in signalling system-wide metabolic and reproductive dysfunction. The far reaching impact of these findings on immune [21], genetic [21] and epigenetic [26] and longevity factors implies that treatment type and agonist administration and duration are key concerns deserving of further close attention. The present findings emphasize concerns derived from other studies of the particular and remarkable sensitivity of females to long term opioid agonist therapies [10-12] and introduce further endocrinologic concerns in relation to the common practice of indefinite opioid agonist treatment [59, 60] as have been previously expressed [10, 35, 38, 61-64]. Overall these findings powerfully and meaningfully inform our appreciation of, and insights into, the experience of females entrapped by the perils of opioid dependence.
Source: Reece Albert Stuart, Thomas Mervyn Rees, Norman Amanda, Hulse GaryKenneth.Dramatic acceleration of reproductive aging, contraction of biochemical fecundity and healthspan-lifespan implications of opioid-induced endocrinopathy—FSH/LH ratio and other interrelationships
Reproductive Toxicology http://dx.doi.org/10.1016/j.reprotox.2016.09.006
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