Intracrine Metabolism and the Development of Lichen Sclerosus: … Chakrabort… · sex hormone...
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Intracrine Metabolism and the Development of Lichen Sclerosus: Sex Hormone Related Insulin Resistance Rima Chakraborty 1 , Colleen Reisz 1,2 1 University of Missouri-Kansas City School of Medicine, 2 Midwest Medical Specialists, Shawnee Mission, KS Introduction Lichen sclerosus (LS) is a chronic inflammatory skin disease that predominantly affects the anogenital region (Barchino-Ortiz, et al 2011). While affecting both genders, the incidence is much greater in women, particularly in the perimenopausal period. New research on peripheral estrogen metabolism (intracrine metabolism) has demonstrated the effects of harmful estrogen metabolism on macrophages and fibroblasts. Communication patterns between estrogen and androgen receptors have shown synergistic and inhibitory effects between receptors classes and underlie how complex estrogen signaling and physiology are in sex steroid dependent tissues. Menopause, the time frame most associated with the onset of lichen sclerosus, is characterized by changes in receptor affinity and communication, aromatase behavior and inflammation. We seek to summarize what is currently known about estrogen metabolism and sex hormone related insulin resistance. We profiled 32 women with lichen sclerosus and outline our findings below. Results The 32 patients are all categorized further by BMI, age and medication history in figure 1.1 below. Discussion Lichen sclerosus has historically been associated with fluctuations in endogenous estrogens (Elchalal et al, 1995). Women at midlife have changing hormone levels that provoke certain prescribing patterns in clinicians. The introduction of pharmaceuticals at midlife may have physiologic consequences that impact sex steroid dependent tissues. The combination of decreasing xenobiotic clearance due to age, fatty liver and changing hormonal status may be further complicated by medications that impact basic metabolic pathways (Marino et al 2011). The recognition of medication induced alteration of the insulin axis, is relatively new and further complicates decision making in individuals with age and physiologic changes in insulin sensitivity. We were particularly interested in medication classes known to negatively affect the insulin axis; we looked specifically for statins, beta blockers, SSRI’s and hormone replacement. While the clinically relevant effects of medication induced insulin resistance are still being debated, it is recognized that these medication classes can impact weight, lipids and inflammation. The concept of insulin resistance and tissue specific consequences outside of diabetes continues to evolve. A recent metanalysis compared rates of new onset DM in different statin use among 113,394 patients and found that different types and doses of statins correlate with different incidence of new onset DM in patients (Navarese et al, 2012). B- blockers have similar hyperglycemic effects (Luna et al, 2001). A recent prospective study of compared non diabetic patients and their risk of developing DM following initiation of B- blocker, thiazide or anti-hypertensive medication and found that 28% risk of developing DM in those 6 years later (Gress et al, 2000). Weight, fatty acid metabolism and inflammation affect how estrogen is metabolized at the macrophage and fibroblast by upregulating aromatase behavior. Changes in fatty acid metabolism from weight, sex steroid levels and the presence of other drugs impact drug clearance. The reduction of drug metaboliiziing enzymes at midlife tends to occur at the same time that prescribing habits increase. Statins, beta blockers, hormones, antidepressants and anti-psychotics are examples of medications that can negatively impact insulin resistance. Future strategies for women with lichen sclerosus may include medication stratification and lifestyle changes designed to reduce insulin resistance and polypharmacy. References Barchino-Ortiz L. Suarez-Fernandez R. Lazaro-Ochaita P. Vulvar Inflammatory Dermatoses. Dermo-Sifiliograficas, Aug 27 2011 Cutolo M. Capellino S. Straub RH. Oestrogens in rheumatic diseases: friend or foe? Rheumatology (Oxford) 2008; 47: (Suppl, 3): iii 2-5 Elchalal U. Gilead L. Vardy DA et al. Treatment of vulvar lichen sclerosus in the elderly: an update. Obstetrics Gynecology Survey 1995; 50: 155-62 Giguere V. Yang N. Segui P. Evans RM. Identification of a new class of steroid hormone receptors. Nature 1988; 331: 91–94. Hart WR. Norris HJ. Helwig EB. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstetric Gynceology 1975:45: 369-77 Herzog B. Cardenas J. Hall RK, Villena JA, Budge PJ, Giguere V. Granner DK, Kralli A. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 2006; 281: 99–106. Hong H. Yang L. Stallcup MR. Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3. J Biol Chem 1999;274: 22618–22626. Johnston SD. Liu X, Zuo F. Eisenbraun TL. Wiley SR. Kraus RJ. Mertz JE. Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Mol Endocrinol 1997;11: 342–352. Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 2003; 100: 12378–12383 Leone TC. Lehman JJ. Finck BN. Schaeffer PJ. Wende AR,.Boudina S. Courtois M. Wozniak DF. Sambandam N. Bernal-Mizrachi C. Chen Z. Holloszy JO. Medeiros DM. Schmidt RE. Saffitz JE. Abel ED. Semenkovich CF. Kelly DP. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 2005; 3: e101. Murphy R. Lichen Sclerosus, Dermatol Clin. 2010; 28: 707-15 Gress, TW. Nieto FJ. Shahar E. Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000 Mar 30;342(13):905-12. Oyama N. Chan I. Neill SM. Hamada T.et al. Autoantibodies to extracelluar matrix protein 1 in lichen sclerosus. Lancet 2003; 362: 118-23 Taylor AH. Guzail M. Al-Azzawi F. Differential expression of oestrogen receptor isoforms and androgen receptor in the normal vulva and vagina compared with vulval lichen sclerosus and chronic vaginitis. Dermatopathology. 2007; 10: 1365-2133 Wang SH. Chic CC, Wong YW. Salim A, Manek S. Wojnarowska F. Genital verrucous carcinoma is associated with lichen sclerosus: a retrospective study and review of the literature. J European Academy Dermatology Venereology. 2010; 24: 815-9 Yki-Järvinen H. Thiazolidinediones, New England Journal of Medicine, 2004; 351:1106-18. Figure 1.3a Figure 1.3b Figure 1.3c Figure 1.3d Figure 1.3e Figure 1.2 Distribution of medication classes Methodology We performed chart reviews on 32 women with severe lichen sclerosus. We included age, BMI and medication history. 9% 40% 18% 12% 21% HRT Sta/n Bblocker SSRI PPI Drug Number of Pa.ents Proton Pump Inhibitors (PPI) 7 BetaBlockers (BBlocker) 6 Selec.ve Serum Reuptake Inhibitors (SSRI) 4 Sta.ns 13 Hormone Replacement Therapy (HRT) 3 Age Number of Pa.ents 4050 4 5160 7 6170 11 7180 5 80 and up 4 BMI Number of Pa.ents Below 18.5 (Underweight) 0 18.524.9 (Normal) 12 2529.9 (Overweight) 9 30 and up (Obese) 11 Figure1.1 Distribution of BMI, Age and Drug classes in 32 patients Figure 1.3 Examples of Lichens Sclerosus r
Transcript of Intracrine Metabolism and the Development of Lichen Sclerosus: … Chakrabort… · sex hormone...
Intracrine Metabolism and the Development of Lichen Sclerosus:!Sex Hormone Related Insulin Resistance!
Rima Chakraborty1, Colleen Reisz1,2!1University of Missouri-Kansas City School of Medicine, 2Midwest Medical Specialists, Shawnee Mission, KS!
Introduction!Lichen sclerosus (LS) is a chronic inflammatory skin disease that predominantly affects the anogenital region (Barchino-Ortiz, et al 2011). While affecting both genders, the incidence is much greater in women, particularly in the perimenopausal period. New research on peripheral estrogen metabolism (intracrine metabolism) has demonstrated the effects of harmful estrogen metabolism on macrophages and fibroblasts. Communication patterns between estrogen and androgen receptors have shown synergistic and inhibitory effects between receptors classes and underlie how complex estrogen signaling and physiology are in sex steroid dependent tissues. Menopause, the time frame most associated with the onset of lichen sclerosus, is characterized by changes in receptor affinity and communication, aromatase behavior and inflammation. We seek to summarize what is currently known about estrogen metabolism and sex hormone related insulin resistance. We profiled 32 women with lichen sclerosus and outline our findings below. !
Results!The 32 patients are all categorized further by BMI, age and medication history in figure 1.1 below. !
Discussion!Lichen sclerosus has historically been associated with fluctuations in endogenous estrogens (Elchalal et al, 1995). Women at midlife have changing hormone levels that provoke certain prescribing patterns in clinicians. The introduction of pharmaceuticals at midlife may have physiologic consequences that impact sex steroid dependent tissues. The combination of decreasing xenobiotic clearance due to age, fatty liver and changing hormonal status may be further complicated by medications that impact basic metabolic pathways (Marino et al 2011). The recognition of medication induced alteration of the insulin axis, is relatively new and further complicates decision making in individuals with age and physiologic changes in insulin sensitivity. ! We were particularly interested in medication classes known to negatively affect the insulin axis; we looked specifically for statins, beta blockers, SSRI’s and hormone replacement. While the clinically relevant effects of medication induced insulin resistance are still being debated, it is recognized that these medication classes can impact weight, lipids and inflammation.!The concept of insulin resistance and tissue specific consequences outside of diabetes continues to evolve. A recent metanalysis compared rates of new onset DM in different statin use among 113,394 patients and found that different types and doses of statins correlate with different incidence of new onset DM in patients (Navarese et al, 2012). B-blockers have similar hyperglycemic effects (Luna et al, 2001). A recent prospective study of compared non diabetic patients and their risk of developing DM following initiation of B-blocker, thiazide or anti-hypertensive medication and found that 28% risk of developing DM in those 6 years later (Gress et al, 2000). !Weight, fatty acid metabolism and inflammation affect how estrogen is metabolized at the macrophage and fibroblast by upregulating aromatase behavior. Changes in fatty acid metabolism from weight, sex steroid levels and the presence of other drugs impact drug clearance. The reduction of drug metaboliiziing enzymes at midlife tends to occur at the same time that prescribing habits increase. Statins, beta blockers, hormones, antidepressants and anti-psychotics are examples of medications that can negatively impact insulin resistance. Future strategies for women with lichen sclerosus may include medication stratification and lifestyle changes designed to reduce insulin resistance and polypharmacy.!
References!Barchino-Ortiz L. Suarez-Fernandez R. Lazaro-Ochaita P. Vulvar Inflammatory Dermatoses. Dermo-Sifiliograficas, Aug 27 2011 !Cutolo M. Capellino S. Straub RH. Oestrogens in rheumatic diseases: friend or foe? Rheumatology (Oxford) 2008; 47: (Suppl, 3): iii 2-5 !Elchalal U. Gilead L. Vardy DA et al. Treatment of vulvar lichen sclerosus in the elderly: an update. Obstetrics Gynecology Survey 1995; 50: 155-62!Giguere V. Yang N. Segui P. Evans RM. Identification of a new class of steroid hormone receptors. Nature 1988; 331: 91–94.!Hart WR. Norris HJ. Helwig EB. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstetric Gynceology 1975:45: 369-77! Herzog B. Cardenas J. Hall RK, Villena JA, Budge PJ, Giguere V. Granner DK, Kralli A. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 2006; 281: 99–106.! Hong H. Yang L. Stallcup MR. Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3. J Biol Chem 1999;274: 22618–22626.! Johnston SD. Liu X, Zuo F. Eisenbraun TL. Wiley SR. Kraus RJ. Mertz JE. Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Mol Endocrinol 1997;11: 342–352.! Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 2003; 100: 12378–12383! Leone TC. Lehman JJ. Finck BN. Schaeffer PJ. Wende AR,.Boudina S. Courtois M. Wozniak DF. Sambandam N. Bernal-Mizrachi C. Chen Z. Holloszy JO. Medeiros DM. Schmidt RE. Saffitz JE. Abel ED. Semenkovich CF. Kelly DP. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 2005; 3: e101.!Murphy R. Lichen Sclerosus, Dermatol Clin. 2010; 28: 707-15 !Gress, TW. Nieto FJ. Shahar E. Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000 Mar 30;342(13):905-12.!Oyama N. Chan I. Neill SM. Hamada T.et al. Autoantibodies to extracelluar matrix protein 1 in lichen sclerosus. Lancet 2003; 362: 118-23 !Taylor AH. Guzail M. Al-Azzawi F. Differential expression of oestrogen receptor isoforms and androgen receptor in the normal vulva and vagina compared with vulval lichen sclerosus and chronic vaginitis. Dermatopathology. 2007; 10: 1365-2133!Wang SH. Chic CC, Wong YW. Salim A, Manek S. Wojnarowska F. Genital verrucous carcinoma is associated with lichen sclerosus: a retrospective study and review of the literature. J European Academy Dermatology Venereology. 2010; 24: 815-9! Yki-Järvinen H. Thiazolidinediones, New England Journal of Medicine, 2004; 351:1106-18.!
Figure 1.3a ! Figure 1.3b !
Figure 1.3c ! Figure 1.3d!
Figure 1.3e !
Figure 1.2 Distribution of medication classes!
Methodology!We performed chart reviews on 32 women with severe lichen sclerosus. We included age, BMI and medication history.!!
9%
40%
18%
12%
21%
HRT
Sta/n
B-‐blocker
SSRI
PPI
Drug Number of Pa.ents
Proton Pump Inhibitors (PPI) 7
Beta-‐Blockers (B-‐Blocker) 6
Selec.ve Serum Reuptake Inhibitors (SSRI) 4
Sta.ns 13
Hormone Replacement Therapy (HRT) 3
Age Number of Pa.ents
40-‐50 4
51-‐60 7
61-‐70 11
71-‐80 5
80 and up 4
BMI Number of Pa.ents
Below 18.5 (Underweight) 0
18.5-‐24.9 (Normal) 12
25-‐29.9 (Overweight) 9
30 and up (Obese) 11
Figure1.1 Distribution of BMI, Age and Drug classes in 32 patients!
Figure 1.3 Examples of Lichens Sclerosus!
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