I do not see how you draw conclusions on the failure of TRT, particularly if one has a normal T. Why would one expect something to "happen" if the level is normal. I can see the link between the Metabolic Syndrome, which is not a disorder, and certain biochemical findings.
Azziz R.
Polycystic Ovary Syndrome Is a Family Affair. J Clin Endocrinol Metab 2008;93(5):1579-81. [For References, Continue Reading
Polycystic Ovary Syndrome Is a Family Affair ]
In this issue of the Journal, Dr. Sir-Petermann and her colleagues (1) report an interesting cross-sectional study of 80 sons of patients with the polycystic ovary syndrome (PCOS), 20 identified in infancy, 31 in childhood, and 29 in adulthood. Using a control population of 56 sons of healthy women, these investigators concluded that the sons of PCOS patients demonstrated early-onset overweightness, observable even in infancy, with the expected hyperinsulinemia and hypercholesterolemia. Furthermore, adult sons were significantly more hyperinsulinemic and insulin resistant than predicted by body mass index (BMI), suggesting that these offspring demonstrate a further defect in insulin action above and beyond that determined by their degree of obesity. This important study clearly demonstrates the heritable aspects of both overweightness and insulin resistance in PCOS and points to the early manifestations of the disorder, namely weight gain, even in infancy and even in the male progeny of PCOS patients.
Significant in this study is the finding of early-onset obesity, evident as early as infancy. Others have previously observed that the development of obesity in adolescence is associated with the self-reported PCOS symptoms in adulthood (2). However, the role of obesity in the development of PCOS remains unclear. In a cross-sectional analysis of 675 unselected women seeking a preemployment health evaluation, we observed a modest, and nonsignificant, increase in the prevalence of PCOS, from 9% to 12%, with increasing BMI (3). In agreement, although the prevalence of obesity varies greatly across the world, various studies of the prevalence of PCOS in different countries with significantly different background rates of obesity yielded similar rates for the prevalence of PCOS (6.5–9%) (3,4,5,6). These data suggest that higher rates of obesity in a population are associated with only modest effects on the overall risk of PCOS.
Data on the role of environmental factors, such as nutrition habits, in the development of PCOS are scant. We observed, in analyzing the features of PCOS over a 15-yr period of time, that the mean BMI and the proportion of individuals with obesity increased in parallel with the change in obesity prevalence in the surrounding general population (3), suggesting that the degree of obesity in PCOS, in part, mirrors that of the proximate population. Alternatively, the rate of obesity among women with PCOS, like that observed in their sons by Sir-Petermann, is generally higher than the prevailing populational rate (2,3,4,5,6). In addition, few differences have been observed in eating habits between women with PCOS and their healthy counterparts. For example, we were unable to detect significant differences in the consumption of total energy, macronutrients, micronutrients, and high-glycemic-index foods between PCOS and race-, age-, and BMI-matched healthy controls (7). Likewise, Carmina et al. (8) were unable to detect differences in total calorie intake and dietary constituents between PCOS women in Italy and the United States, except for a higher saturated fat in U.S. women, despite the significantly higher BMI of U.S. patients. These results suggest that although environmental factors, such as eating habits, may determine the degree of obesity in PCOS, the higher rate of obesity in PCOS relative to that of the surrounding population and the early development of obesity observed in women with PCOS (or, as in this study, in the sons of women with PCOS) may be due more to inherited than to environmental factors.
The overall higher prevalence of obesity in PCOS, despite the absence of significant differences in dietary intake and regardless of the overall prevalence of obesity in the surrounding population, and the early onset of the overweightness, suggests the importance of genetic factors. However, to date, only a few obesity-related genes, such as PPAR?, leptin, leptin receptor, and adiponectin have been examined in PCOS (9). Increased efforts should be made to thoroughly examine those genes modulating the development of obesity and fat mass in humans, including genes encoding for factors regulating food and energy intake and satiety (e.g. neuropeptide Y, ghrelin, cholecystokinin, peptide YY), genes encoding for factors regulating energy expenditure (e.g. members of the ?-adrenoceptor gene family and uncoupling proteins), and genes encoding for factors implicated in adipogenesis [e.g. the fat mass and obesity-associated (FTO) gene] (10,11).
Nonetheless, the study of PCOS genetics is not without its challenges. PCOS should be considered a common, complex genetic disorder, as are other conditions such as type 2 diabetes mellitus (DM), schizophrenia, and asthma. Such common diseases, including PCOS, appear to have a complex, multifactorial etiology, in which multiple predisposing genes, not just one gene, interact with environmental factors to produce disease. A major challenge to gene-finding efforts in complex diseases is that each gene typically contributes modestly to disease risk. For example, most of the recently discovered genes for type 2 DM affect risk by only 25–35% (12), necessitating large sample sizes for adequate power to discover the genes. PCOS genetics is also faced with other hurdles unique to the syndrome, such as impaired fertility potentially leading to small family sizes, lack of a clear phenotype in men (notwithstanding the observations of Sir-Petermann and colleagues) and in prepubertal and menopausal women, and the absence of universally accepted diagnostic criteria (13). Although several positive results have been reported in PCOS, no gene or genes is universally accepted as important in PCOS pathogenesis. This is the result of inadequate analysis of the genes, because often only one or two variants are analyzed, and of the small size of the cohorts in many studies. Equally contributing has been the relative lack of a systematic effort to replicate positive results.
As genetic epidemiology advances, the approach of testing one variant per gene is being replaced by analyzing candidate genes completely with several haplotype-tagging single-nucleotide polymorphisms as well as testing entire pathways or entire genomes with many variants. To mitigate the increased probability of false-positive associations due to multiple testing, it is essential that positive reports be confirmed before results can be widely accepted. Unfortunately, few efforts have been made in this regard in the study of PCOS genetics. Replication studies in the investigation of the genetics of complex disorders, including PCOS, are essential elements in our progress toward understanding the genetic basis of these pervasive disorders. For example, an initial report found association with PCOS of a promoter variant in the gene for 17?-hydroxysteroid dehydrogenase type 5 (14), a biologically plausible candidate. Yet, a study in a much larger cohort demonstrated no evidence of this association (15). It is thus evident that advances in high-throughput genotyping and analysis will need to be accompanied by greater replication efforts in PCOS genetics. Indeed, the great progress in type 2 DM has been made possible by the ample number of replication efforts (12). Notably, proper replication studies need to include a significantly greater number of subjects than the initial study (16), a major problem considering the paucity of large genetic databases available for the study of PCOS.
As important as the findings of the study of Sir-Petermann are, also interesting are what the investigators did not observe. Despite evidence that the BMIs of the infants studied were higher than that of sons of normal women, the weights or gestational ages at birth did not differ between the sons of PCOS and their healthy counterparts. Various investigators have suggested that one cohort of girls at risk for developing premature adrenarche, insulin resistance, or PCOS are those individuals that are born small for gestational age (SGA) (17,18). Sir-Petermann and her colleagues had previously reported that in 47 infants born from singleton pregnancies in women with PCOS, the prevalence of SGA infants was significantly higher (12.8 vs. 2.8%, respectively), compared with 180 infants born to healthy controls (19). Alternatively, other investigators using data from a longitudinal, population-based study of a cohort of women born in 1966 in northern Finland did not observe an association between weight at birth, gestational age, SGA, or growth retardation at birth with self-reported symptoms of PCOS (2). The absence of a higher prevalence of SGA or low-birth-weight infants in the sons of PCOS women, who otherwise appear to demonstrate a higher frequency of impaired insulin action, suggests that the presence of an intrauterine impairment in growth is not associated with the development of the insulin resistance of PCOS or, alternatively, may selectively affect female fetuses, such that SGA may be an etiological factor in a subset of PCOS women. Further investigation of the role of the intrauterine environment in the development of PCOS, particularly in females, is needed.
Finally, the results of this study highlight the significant economic burden that PCOS and its associated morbidities have. In the United States, we estimate that at a minimum 4 million women are affected and that the economic burden of these women just in their premenopausal years is conservatively 4.4 billion dollars (in 2004 figures) (20). A cursory estimate of the cost of PCOS in menopausal women suggests that an additional 9.5 billion dollars would be spent related to the excess rate of DM, cerebrovascular accidents, and cardiovascular disease (CVD) (Azziz, R., and K. D. Gregory, unpublished). The economic burden related to PCOS would rise even further if the disorder were confirmed to be associated with a net increase in the incidence of metabolic disorders and CVD in the sons of women with PCOS, as suggested by the data of Sir-Petermann and colleagues.
The symptoms of PCOS in an index patient or in the mother or sister, arguably the earliest indicator of an increased risk for DM and CVD, may provide an opportunity for early risk factor detection and intervention. For example, women with irregular menses demonstrate an increased risk of DM and CVD (21,22), an effect the investigators attributed primarily to the predominant role PCOS plays in menstrual dysfunction. Consequently, the presence of menstrual irregularities or symptoms of hyperandrogenism or PCOS in female members of a family should be considered an additional risk factor for metabolic dysfunction, type 2 DM, and CVD in all family members.
And so, PCOS is a family affair. Sisters, brothers, fathers, mothers, daughters, and now even sons of women with PCOS have been found to have a higher risk for exhibiting either the hyperandrogenemic or metabolic traits of the disorder. In addition, the data of Sir-Petermann and colleagues (1) suggest that the development of overweightness and obesity in childhood or adolescence, in the absence of gross abnormalities in birth weight, may be one of the earliest signs of the disorder. Currently, most data appear to suggest that the development of obesity in PCOS families is primarily driven by genetic factors, although the degree and overall prevalence of obesity in the disorder may reflect, to a significant extent, the surrounding environment. There is an urgent need to continue to identify potential candidate genes in PCOS, taking into account the fact that in this, like other complex traits, most genes will have relatively modest effects on the development of the disorder when considered individually. Likewise, there is a significant need to develop multiple large consortia to collect and phenotype sufficient numbers of patients to discover putative genes and participate in the necessary replication studies. While I congratulate Dr. Sir-Petermann and her colleagues on a well thought-out investigation, I also look forward to the replication study that will confirm their observations and extend them to gene identification.
Recabarren SE, Sir-Petermann T, Rios R, et al.
Pituitary and Testicular Function in Sons of Women with Polycystic Ovary Syndrome from Infancy to Adulthood. J Clin Endocrinol Metab 2008;93(9):3318-24.
Pituitary and Testicular Function in Sons of Women with Polycystic Ovary Syndrome from Infancy to Adulthood -- Recabarren et al. 93 (9): 3318 -- Journal of Clinical Endocrinology & Metabolism
Context: An important proportion of male members of polycystic ovary syndrome (PCOS) families exhibit insulin resistance and related metabolic defects. However, the reproductive phenotypes in first-degree male relatives of PCOS women have been described less often.
Objective: The objective of the study was to evaluate the pituitary-testicular function in sons of women with PCOS during different stages of life: early infancy, childhood, and adulthood. Design: Eighty sons of women with PCOS (PCOSS) and 56 sons of control women without hyperandrogenism (CS), matched for age, were studied. In all subjects, the pituitary-gonadal axis was evaluated by a GnRH agonist test (leuprolide acetate, 10 {micro}g/kg sc). Serum anti-Mullerian hormone (AMH) and inhibin B were used as Sertoli cell markers. Serum concentrations of gonadotropins, steroid hormones, and SHBG were also determined. A semen analysis was performed.
Results: Basal concentrations of gonadotropins, sex steroids, and inhibin B were comparable between PCOSs and CS during early infancy, childhood, and adulthood. Similar results in stimulated gonadotropin and sex steroid concentrations were observed. However, AMH serum concentrations were higher in PCOSs compared with CS during early infancy [925.0 (457.3-1401.7) vs. 685.6 (417.9-1313.2) pmol/liter, P = 0.039] and childhood [616.3 (304.6-1136.9) vs. 416.5 (206.7-801.2) pmol/liter, P = 0.007). Sperm-count analysis was similar between both groups.
Conclusions: AMH concentrations are increased in prepubertal sons of women with PCOS, suggesting that these boys may show an increased Sertoli cell number or function during infancy and childhood. However, this does not seem to have a major deleterious effect on sperm production.
