Does Pioglitazone negatively impact breast development?
And a bit about cancer
Pioglitazone is an anti-diabetic medication that activates PPARγ systemically, reducing insulin resistance, gluconeogenesis and overall blood sugar, and increasing fat uptake and adipogenesis. High insulin resistance in transgender females is associated with android fat distribution/higher WHR1. It has been shown to lower visceral fat2 and WHR even in patients who’s overall BMI remained the same3. It seems to protect subcutaneous fat in a way similar to estrogen4. There has even been one documented case of pioglitazone use to achieve female fat distribution in a transgender patient in the medical literature5. Thus Pioglitazone may be used to improve fat distribution and to facilitate the growth of fatty tissue in the breast, improving breast size.
Let us investigate some more…
Aside from fatty tissue, there is also mammary epithelial tissue in the breast which makes up the lobules as seen on the diagram above. PPARγ is the master regulator of adipocyte differentiation and can even convert fibroblasts into adipocytes in vitro6. Therefore could stem cells be differentiated into adipose tissue instead of mammary tissue, causing a negative impact on lobule development? This is not the case since adipocytes develops from mesenchymal stem cells which are not multipotent for epithelial cells, and conversely the mammary epithelial cells develop from mammary stem cells which are not multipotent for adipocytes.
Nonetheless, PPARγ agonists including 15d-PGJ2 and ciglitazone have been shown to have an anti-proliferative effect on mammary epithelium in vitro7. However, antiproliferative effects of PPARγ agonists have also been seen in cells that do not express PPARγ8910. Furthermore, transgenic mice that express a constitutively active form of PPARγ in mammary tissue (but have not been treated with PPARγ agonists) were indistinguishable from their wild-type littermates, with no effect on mammary cell proliferation11. Thus we can conclude that the antiproliferative effect of PPARγ agonists is independent of their action on PPARγ.
All of the above agonists including 15d-PGJ2 and thiazolidinediones such as ciglitazone and pioglitazone have anti-inflammatory action, specifically they inhibit NF-κB121314. NF-κB has been shown to upregulate proliferation of cells, especially that of mammary epithelial cells15 – thus this inhibitory action may explain their antiproliferative effects.
PPARγ in transgenic mice has caused a significantly increased rate of cancer progression16. On the other hand, NF-κB (which promotes growth/proliferation) is hyperactivated in human breast cancer, and its inhibition slows the rate of tumor development17. One paper suggests that the anti-cancer activity of PPARγ agonists has noting to do with their action at PPARγ18. Thiazolidinediones have exhibited both anti- and pro- cancer activity in studies, and this may make sense given the above context.
Conclusions?
The anticancer activity of PPARγ agonists may be explained by their inhibition of NF-κB or other off-site activity, and the pro-cancer activity may be explained by agonism of PPARγ.
PPARγ agonists may have an anti-proliferative effect on mammary epithelial cells, although this seems to be independent of their PPARγ activity and is more likely to be caused by inhibition of NF-κB.
TL;DR Pioglitazone probably has a negative impact on the development of breast glands.
Bretherton I, Spanos C, Leemaqz SY, et al. Insulin resistance in transgender individuals correlates with android fat mass. Ther Adv Endocrinol Metab. 2021;12:2042018820985681. doi:10.1177/2042018820985681
Ibáñez L, López-Bermejo A, del Rio L, Enríquez G, Valls C, de Zegher F. Combined low-dose pioglitazone, flutamide, and metformin for women with androgen excess. J Clin Endocrinol Metab. 2007;92(5):1710-1714. doi:10.1210/jc.2006-2684
Shadid S, Jensen MD. Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity. Diabetes Care. 2003;26(11):3148-3152. doi:10.2337/diacare.26.11.3148
van Harmelen V, Dicker A, Rydén M, et al. Increased lipolysis and decreased leptin production by human omental as compared with subcutaneous preadipocytes. Diabetes. 2002;51(7):2029-2036. doi:10.2337/diabetes.51.7.2029
Malik I, Barrett J, Seal L. Thiazolindinediones are useful in achieving female type fat distribution in male to female transsexuals. Endocr Abstr. 2009;19. Accessed September 29, 2022. https://www.endocrine-abstracts.org/ea/0019/ea0019p74
Tontonoz, P.; Hu, E.; Spiegelman, B. M. Stimulation of Adipogenesis in Fibroblasts by PPARγ2, a Lipid-Activated Transcription Factor. Cell 1994, 79 (7), 1147–1156. https://doi.org/10.1016/0092-8674(94)90006-X.
Yee, L. D.; Guo, Y.; Bradbury, J.; Suster, S.; Clinton, S. K.; Seewaldt, V. L. The Antiproliferative Effects of PPARgamma Ligands in Normal Human Mammary Epithelial Cells. Breast Cancer Res. Treat. 2003, 78 (2), 179–192. https://doi.org/10.1023/a:1022978608125.
Abe, A.; Kiriyama, Y.; Hirano, M.; Miura, T.; Kamiya, H.; Harashima, H.; Tokumitsu, Y. Troglitazone Suppresses Cell Growth of KU812 Cells Independently of PPARgamma. Eur. J. Pharmacol. 2002, 436 (1–2), 7–13. https://doi.org/10.1016/s0014-2999(01)01577-1.
Palakurthi, S. S.; Aktas, H.; Grubissich, L. M.; Mortensen, R. M.; Halperin, J. A. Anticancer Effects of Thiazolidinediones Are Independent of Peroxisome Proliferator-Activated Receptor Gamma and Mediated by Inhibition of Translation Initiation. Cancer Res. 2001, 61 (16), 6213–6218.
Chawla, A.; Barak, Y.; Nagy, L.; Liao, D.; Tontonoz, P.; Evans, R. M. PPAR-Gamma Dependent and Independent Effects on Macrophage-Gene Expression in Lipid Metabolism and Inflammation. Nat. Med. 2001, 7 (1), 48–52. https://doi.org/10.1038/83336.
Saez, E.; Rosenfeld, J.; Livolsi, A.; Olson, P.; Lombardo, E.; Nelson, M.; Banayo, E.; Cardiff, R. D.; Izpisua-Belmonte, J. C.; Evans, R. M. PPARγ Signaling Exacerbates Mammary Gland Tumor Development. Genes Dev. 2004, 18 (5), 528–540. https://doi.org/10.1101/gad.1167804.
Jang, H.-Y.; Hong, O.-Y.; Youn, H. J.; Kim, M.-G.; Kim, C.-H.; Jung, S. H.; Kim, J.-S. 15d-PGJ2 Inhibits NF-ΚB and AP-1-Mediated MMP-9 Expression and Invasion of Breast Cancer Cell by Means of a Heme Oxygenase-1-Dependent Mechanism. BMB Rep. 2020, 53 (4), 212–217. https://doi.org/10.5483/BMBRep.2020.53.4.164.
Kaplan, J.; Nowell, M.; Chima, R.; Zingarelli, B. Pioglitazone Reduces Inflammation through Inhibition of NF-ΚB in Polymicrobial Sepsis. Innate Immun. 2014, 20 (5), 519–528. https://doi.org/10.1177/1753425913501565.
Chima, R. S.; Hake, P. W.; Piraino, G.; Mangeshkar, P.; Denenberg, A.; Zingarelli, B. Ciglitazone Ameliorates Lung Inflammation by Modulating the IKK/NF-ΚB Pathway Following Hemorrhagic Shock. Crit. Care Med. 2008, 36 (10), 2849–2857.
Brantley, D. M.; Chen, C. L.; Muraoka, R. S.; Bushdid, P. B.; Bradberry, J. L.; Kittrell, F.; Medina, D.; Matrisian, L. M.; Kerr, L. D.; Yull, F. E. Nuclear Factor-KappaB (NF-KappaB) Regulates Proliferation and Branching in Mouse Mammary Epithelium. Mol. Biol. Cell 2001, 12 (5), 1445–1455. https://doi.org/10.1091/mbc.12.5.1445.
Saez, E.; Rosenfeld, J.; Livolsi, A.; Olson, P.; Lombardo, E.; Nelson, M.; Banayo, E.; Cardiff, R. D.; Izpisua-Belmonte, J. C.; Evans, R. M. PPARγ Signaling Exacerbates Mammary Gland Tumor Development. Genes Dev. 2004, 18 (5), 528–540. https://doi.org/10.1101/gad.1167804.
Wang, W.; Nag, S. A.; Zhang, R. Targeting the NFκB Signaling Pathways for Breast Cancer Prevention and Therapy. Curr. Med. Chem. 2015, 22 (2), 264–289.
Palakurthi, S. S.; Aktas, H.; Grubissich, L. M.; Mortensen, R. M.; Halperin, J. A. Anticancer Effects of Thiazolidinediones Are Independent of Peroxisome Proliferator-Activated Receptor Gamma and Mediated by Inhibition of Translation Initiation. Cancer Res. 2001, 61 (16), 6213–6218.
Doubt the impact of pioglitazone on NF-κB is relevant for breast development. ESTRADIOL ITSELF suppresses NF-κB.
https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr2255 Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? "Several studies have shown that E2 can inhibit the activity of NF-κB and thereby increase apoptosis. For example, Osipo and colleagues [35] reported that, in tamoxifen-resistant MCF-7 tumors, E2 treatment almost completely down-regulated the level of the NF-κB p65 subunit protein, which correlated with the anti-proliferative and pro-apoptotic effects of E2 in this model system".
https://dspace.library.uu.nl/handle/1874/8772 Inhibition of NF-κB transcriptional activity by the estrogen receptor - Insights into the molecular mechanism
The closest thing I found: rosiglitazone inhibits estrogen-independent breast growth induced by conjugated linoleic acid which is associated with metabolic syndrome.
https://www.pnas.org/doi/full/10.1073/pnas.1210527109 (Diet-induced metabolic change induces estrogen-independent allometric mammary growth)
"Lifetime breast cancer risk reflects an unresolved combination of early life factors including diet, body mass index, metabolic syndrome, obesity, and age at first menses. In parallel, the onset of allometric growth by the mammary glands around puberty is widely held to be estrogen (E)-dependent. Here we report that several physiological changes associated with metabolic syndrome in response to a diet supplemented with the trans-10, cis-12 isomer of conjugated linoleic acid lead to ovary-independent allometric growth of the mammary ducts. The E-independence of this diet-induced growth was highlighted by the fact that it occurred both in male mice and with pharmacological inhibition of either E receptor function or E biosynthesis. Reversal of the metabolic phenotype with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone abrogated diet-induced mammary growth. A role for hyperinsulinemia and increased insulin-like growth factor-I receptor (IGF-IR) expression during mammary growth induced by the trans-10, cis-12 isomer of conjugated linoleic acid was confirmed by its reversal upon pharmacological inhibition of IGF-IR function. Diet-stimulated ductal growth also increased mammary tumorigenesis in ovariectomized polyomavirus middle T-antigen mice. Our data demonstrate that diet-induced metabolic dysregulation, independently of ovarian function, stimulates allometric growth within the mammary glands via an IGF-IR-dependent mechanism".
Breasts are mainly fat so it would be best to find studies about it. Pioglitazone stimulates creation of new fat cells in gluteofemoral depot but not abdominal visceral or even abdominal subcutaneous (which despite being subcutaneous is detrimental for health unlike gluteofemoral), depending on the study, reduces already existing abdominal fat. Interestingly, it increases pericardial fat which is visceral, but "this increase in pericardial fat volume did not negatively affect myocardial function after 24 wk", so it's not just lower body fat.