Abstract
The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40–65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.
Highlights
IntroductionFFiigguurree11..SScchheemmaattiiccoofftthheessyynntthheessiissooffsseexx sstteerrooiiddhhoorrmmoonneessffrroommcchhoolleesstteerrooll..IInn nnoorrmmaall bbrreeaassttttiissssuuee,, pprreeggnneenneess((pprrooggeessteterroonneeisisaapprreeggnneennee))aarreeththeepprreeddoommininaannttccoommppoouunnddss. .AAllloofftthhee44--pprreeggnneenneess((nnoott sshhoowwnn))ccaannbbeeirirerevveerrssibiblylyccoonnvveerrteteddtoto55αα-p-prereggnnaannee(r(erespspeecctitviveelyly))vviaia55αα-r-eredduucctatassee. .EExxppeerrimimeennttaall ssttuuddiieessiinnmmiicceehhaavveesshhoowwnntthhaatttthheettwwoommeettaabboolliitteess,, 55ααPP aanndd 33ααHHPP,,sshhoowwtthheeggrreeaatteessttddiiffffeerreenncceess bbeettwweeeenn ttuummoorr aanndd nnoonn--ttuummoorr ssaammpplleess;; tthhee rraattiioo ooff 55ααPP//33ααHHPP iiss mmoorree tthhaann 1100--ffoolldd hhiigghheerr iinn bbrreeaasstt ttuummoorr ttiissssuueess aanndd 33--ttiimmeess hhiigghheerr iinn ccirirccuulalattiioonn,, ccoommppaarriinngg mmiiccee tthhaatt ddeevveellooppeedd ttuummoorrss ttoo mmiiccee wwitithhoouutt ttuummoorrss [18]
We evaluated potential confounding by assessing the relationship between reproductive and other risk factors previously known to be associated with mammographic breast density (MBD), terminal duct lobular unit (TDLU) involution, and progesterone and progesterone metabolites
Progesterone levels were observed in the highest concentration (14,405 progesterone-related metabolites levels (pmol/L)); whereas, among follicular phase and postmenopausal women, 17α-hydroxypregnenolone levels were observed in the highest concentrations (3414 pmol/L and 2625 pmol/L, respectively)
Summary
FFiigguurree11..SScchheemmaattiiccoofftthheessyynntthheessiissooffsseexx sstteerrooiiddhhoorrmmoonneessffrroommcchhoolleesstteerrooll..IInn nnoorrmmaall bbrreeaassttttiissssuuee,, pprreeggnneenneess((pprrooggeessteterroonneeisisaapprreeggnneennee))aarreeththeepprreeddoommininaannttccoommppoouunnddss. .AAllloofftthhee44--pprreeggnneenneess((nnoott sshhoowwnn))ccaannbbeeirirerevveerrssibiblylyccoonnvveerrteteddtoto55αα-p-prereggnnaannee(r(erespspeecctitviveelyly))vviaia55αα-r-eredduucctatassee. .EExxppeerrimimeennttaall ssttuuddiieessiinnmmiicceehhaavveesshhoowwnntthhaatttthheettwwoommeettaabboolliitteess,, 55ααPP aanndd 33ααHHPP,,sshhoowwtthheeggrreeaatteessttddiiffffeerreenncceess bbeettwweeeenn ttuummoorr aanndd nnoonn--ttuummoorr ssaammpplleess;; tthhee rraattiioo ooff 55ααPP//33ααHHPP iiss mmoorree tthhaann 1100--ffoolldd hhiigghheerr iinn bbrreeaasstt ttuummoorr ttiissssuueess aanndd 33--ttiimmeess hhiigghheerr iinn ccirirccuulalattiioonn,, ccoommppaarriinngg mmiiccee tthhaatt ddeevveellooppeedd ttuummoorrss ttoo mmiiccee wwitithhoouutt ttuummoorrss [18]. The comprehensive study of progesterone and its metabolites among pre- and postmenopausal women has only recently become technically feasible with highly reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods [30]. Leveraging this recently developed assay [30], we aimed to explore cross-sectional relationships between serum progesterone/progesterone metabolites, with a particular emphasis on the metabolites 5αP, 3αHP, and the ratio of 5αP-to-3αHP, with MBD and TDLU involution among women, attending a mammographic screening program, who were subsequently referred for image-guided diagnostic breast biopsy. As the biological effects of progesterone may be dependent upon dose and duration of exposure to other hormones, like estrogen [7], we utilized pre-existing data on serum unconjugated estradiol levels [19] among these women and evaluated the progesterone-to-estradiol ratio
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