Mechanisms of intergenerational transmission of polycystic ovary syndrome.

Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine-metabolic environment that adversely affects the female fetus and long-term offspring health. Prenatal testosterone treatment in monkeys and sheep have been particularly crucial in our understanding of developmental programming of PCOS because organ system differentiation in these species, as in humans, occurs during fetal life. These animal models, along with altricial rodents, produce permanent PCOS-like phenotypes variably characterized by LH hypersecretion from reduced steroid-negative feedback, hyperandrogenism, ovulatory dysfunction, increased adiposity, impaired glucose-insulin homeostasis and other metabolic abnormalities. The review concludes that DoHAD underlies the phenotypic expression of PCOS through an altered maternal endocrine-metabolic environment that can induce epigenetic modifications of fetal genetic susceptibility to PCOS after birth. It calls for improved maternal endocrine-metabolic health of PCOS women to lower their risks of pregnancy-related complications and to potentially reduce intergenerational susceptibility to PCOS and its metabolic derangements in offspring.

Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism. DESIGN: A double-blind, placebo-controlled randomized clinical trial. SETTING: An academic medical center. PATIENT(S): Twelve normal-weight women with PCOS and 12 age- and body mass index-matched controls. INTERVENTION(S): Women underwent circulating hormonal and metabolic determinations, intravenous glucose tolerance testing, total body dual-energy roentgenogram absorptiometry, and SC abdominal fat biopsy. Interventions were repeated in women with PCOS after 6-month administration of flutamide (125 mg orally daily) vs. placebo. MAIN OUTCOME MEASURE(S): Clinical parameters and lipid accumulation in newly formed adipocytes derived from SC abdominal ASCs in vitro were compared between controls and the women with PCOS receiving flutamide vs. placebo. RESULTS: Serum luteinizing hormone and androgen levels as well as lipid accumulation in newly formed SC abdominal adipocytes were greater in the women with PCOS than controls. Flutamide vs. placebo reduced percent android fat, lowered serum log low-density lipoprotein and log non-high-density lipoprotein levels, and increased fasting circulating glucose levels. In all women with PCOS, changes in percent android fat positively correlated with serum log non-high-density lipoprotein and log low-density lipoprotein levels, with correlations influenced by serum free testosterone levels. Flutamide vs. placebo also attenuated lipid accumulation in newly-formed PCOS SC abdominal adipocytes in vitro relative to controls, which was unrelated to serum lipid levels. CONCLUSION: Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation in newly-formed adipocytes derived from SC abdominal ASCs in vitro, and alters glucose-lipid homeostasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT01889199 (URL, clinicaltrials.gov; date of registration, 6/28/2013; enrollment date of first subject, 6/28/2013).

Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls. INTERVENTION(S): Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. MAIN OUTCOME MEASURE(S): PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR). RESULT(S): Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si. CONCLUSION: In normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake.

Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women.

CONTEXT: Increased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women. OBJECTIVE: This work examines whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women. METHODS: This prospective cohort study took place in an academic center and comprised 19 normal-weight PCOS women and 21 age- and body mass index-matched controls. Interventions included circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. Serum T/A4 ratios, hormone/metabolic measures, and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si). RESULTS: Increased serum T/A4 ratios (P = .040) and log adipose-IR values (P = .002) in PCOS women vs controls were accompanied by AKR1C3 messenger RNA overexpression of PCOS adipocytes matured in vitro (P = .016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TGs: R = -0.65, P = .002) and the TG index (R = -0.57, P = .011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R = -0.57, P = .013) and TG index (R = -0.50, P = .036), respectively, without significant relationships with other metabolic measures. CONCLUSION: An elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.