Aging, the menopausal transition, and hormone replenishment therapy: retrieval of confidence and compliance.

The negative health consequences of age and the postmenopausal hypoestrogenic state and their clinical management are described in this paper. While some dysfunctional elements are irreversibly entrained, others can be modified by an updated menopausal hormone therapy (MHT) strategy reflecting revision and reassessment of the initial Women's Health Initiative (WHI) reports. However, until that positive outcome is realized, menopausal women and their healthcare providers must re-establish willingness to utilize these effective strategies. This reluctance is fueled by persistent mistaken application of WHI results that reflect the bundled risk and benefits of MHT in asymptomatic women aged 50-79 (average age 63), as opposed to women in their 40s and 50s who initiate therapy because of vasomotor symptoms. The absolute risk of adverse outcomes is much lower and the benefits dramatically higher in these younger women. In addition, newer FDA-approved formulations, lower dosage regimens, and transdermal delivery methodologies offer wider choice of approaches and promise even greater safety. The positive and negative lessons of the WHI have been learned and can be applied effectively.

Intrauterine Reprogramming of the Polycystic Ovary Syndrome: Evidence from a Pilot Study of Cord Blood Global Methylation Analysis.

Polycystic ovary syndrome (PCOS) affects 5-15% of women. PCOS is a heterogeneous disorder displaying endocrine, metabolic, and reproductive dysfunction and cardiovascular risk manifestations. Evidence of heritability exists, but only a portion of the genetic transmission has been identified by genome-wide association studies and linkage studies, suggesting epigenetic phenomena may play a role. Evidence implicates intrauterine influences in the genesis of PCOS. This was a pilot study that aimed at identifying an epigenetic PCOS reprogramming signature by profiling the methylation of the DNA extracted from umbilical cord blood (UCB) from 12 subjects undergoing in vitro fertilization. Six subjects were anovulatory PCOS women diagnosed by Rotterdam criteria and six ovulatory non-PCOS women matched for age and body mass index. UCB was collected at delivery of the placenta; the DNA was extracted and submitted to methylation analysis. A differential methylation picture of prevalent hypomethylation affecting 918 genes was detected. Of these, 595 genes (64.8%) carried single or multiple hypomethylated CpG dinucleotides and 323 genes (35.2%) single or multiple hypermethylated CpG dinucleotides. The Ingenuity Pathway Analysis (IPA) online platform enlisted 908 of the 918 input genes and clustered 794 of them into 21 gene networks. Key features of the primary networks scored by IPA included carbohydrate and lipid metabolism, neurotransmitter signaling, cardiovascular system development and function, glycosaminoglycan signaling regulation and control of amino acid biosynthesis. Central to the network activities were genes controlling hormonal regulation (ESR1), mitochondrial activity (APP, PARK2), and glucose metabolism (INS). Regulatory pathways such as G-protein coupled receptor signaling, inositol metabolism, and inflammatory response were also highlighted. These data suggested the existence of a putative "PCOS epigenomic superpathway" with three main components: glucotoxic, lipotoxic, and inflammatory. If our results are confirmed, they hint at an epigenetic at risk PCOS "signature" may thus exist that may be identifiable at birth. Additional studies are needed to confirm the results of this pilot study.