Phosphodiesterase 4 inhibition as a potential new therapeutic target in obese women with polycystic ovary syndrome.
BACKGROUND
Phosphodiesterase (PDE) enzymes, including members of PDE4, have been investigated in the regulation of endocrine and reproductive functions of ovaries. In addition, selective inhibition of PDE4 enzyme has recently been implicated in the regulation of metabolism with positive effects on glucose homeostasis and weight reduction.


OBJECTIVE
The aim of this study was to evaluate whether the PDE4 inhibitor roflumilast affects body weight and hormonal and metabolic status in obese women with polycystic ovary syndrome (PCOS). Design/Participants/Main Outcome Measures: A 12-week prospective randomized open-label study was conducted with 36 obese women with PCOS diagnosed by the National Eunice Kennedy Shriver Institute of Child Health and Human Development criteria that had been pretreated with metformin (MET). They were randomized to MET 1000 mg twice a day or combined treatment (COM) with MET 1000 mg twice a day and roflumilast 500 μg every day. The primary outcome was change in anthropometric measures of obesity.


RESULTS
Thirty-one patients (aged 33.8 ± 7.4 y, twice a day 36.4 ± 5.1 kg/m(2), mean ± SD) completed the study: 16 on MET and 15 on COM. Subjects treated with COM lost on average 4.2 ± 2.8 kg compared with a 0.9 ± 2.5 kg weight gain in the MET group (P = .025). Body mass index decreased for 1.6 ± 1.1 kg/m(2) in COM arm compared with increase for 0.9 ± 2.4 kg/m(2) in the MET arm (P = .046). Visceral adipose tissue area as assessed by dual-energy x-ray absorptiometry decreased from 136.7 ± 37.8 to 121.2 ± 36.2 cm(2) in the COM arm compared with an increase from 155.3 ± 61.9 to 166.7 ± 67.2 cm(2) in the MET arm (P = .02). From baseline to study end, both treatment interventions resulted in a significant reduction of androstenedione (P = .013), free T (P = .002), and homeostasis model assessment for insulin resistance score (P = .027) and a significant increase in SHBG (P = .024), although the between-treatment differences of the changes have not been statistically significant yet.


CONCLUSIONS
Roflumilast added to metformin reduced body weight in obese women with PCOS, primarily due to a loss of fat mass.
Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana 1525, Slovenia.
Mojca
M
Jensterle
Tomaz
T
Kocjan
Andrej
A
Janez
D000328:Adult; D000631:Aminopyridines / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003521:Cyclopropanes / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D008597:Menstrual Cycle / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000008:administration & dosage; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000150:complications* / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D011085:Polycystic Ovary Syndrome / Q000150:complications* / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D007328:Insulin; D058988:Phosphodiesterase 4 Inhibitors; D012738:Sex Hormone-Binding Globulin; C424423:Roflumilast; D013739:Testosterone; D008687:Metformin