PCOS, BPA and Endocrine Disruptors, Part Three by Jeffrey Dach MD

This is part three of a series. For Part One Click Here. For Part Two, Click Here.

At the May 16 A4M Meeting in Orlando, Felice Gersh MD gave an excellent talk on PCOS, which I will attempt to summarize in this article.  Dr. Gersh in an integrative OB/Gyne in Irvine California.

What is PCOS ?

Poly Cystic Ovary Syndrome – PCOS

PCOS is characterized by anovulatory cycles, increased testosterone and DHEA levels causing hirsutism and acne, insulin resistance, and increased inflammation in the body.  In addition, recent studies show dysfunctional Estrogen Receptors (ER alpha and ER Beta)  and Progesterone receptors.(1)

Endocrine Disruptor BPA  Bisphenol A

Dr Gersh was very blunt about the cause of PCOS, linking neonatal exposure to the endocrine disruptor chemical BPA (Bisphenol-A) to the increasing epidemic of PCOS affecting 10-20% of the female population.(1-7)

Dr Gersh pointed out that in experimental animals, neonatal exposure to BPA (Bisphenol-A) results in a PCOS-like syndrome in adulthood.  In addition, there is elevated BPA levels in PCOS patients.(6)  Genetic studies show polymorphism or genetic mutations in the Estrogen receptors.(4)

The altered Estrogen Receptors leads to altered follicle development and explains the anovulory cycles.

Bis-Phenol-A Physiologic Effects 

BPA-Endocrine Disruptor

1) Reduces the number of oocytes
2) Lowers successful number of births
3) Changes gene expression – differences only apparent after
estrogen exposure.
4) Reduces the function of Estrogen Receptor Beta
5) Negatively affects mitochondrial function
6) Alters hypothalamic pituitary- gonadal axis Increases testosterone,
7) lowers progesterone,
8) alters GnRH secretion
9) Increases glucocorticoids,
10) heightens response to stress, elevates levels of anxiety

BPA is Everywhere !

Bisphenol A is found in plastics and in the plastic lining of canned foods (see above image) and we are unfortunately exposed to huge quantities of it in our everyday life.

Early Environmental Pioneers

Early pioneers in the field who warned us about the effects of endocrine disrupting chemicals in the environment were Rachel Carson in her 1962 book, Silent Spring, and Theo Coburn in her book, Our Stolen Future: Threatening Our Fertility.

This is Part Three of a series.
For Part One Click Here.
For Part Two, Click Here.

More Links:

Dr. Coburn web site.
Our Stolen Future Web site.

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
https://jeffreydachmd.com
http://www.drdach.com
http://www.naturalmedicine101.com
http://www.bioidenticalhormones101.com/
http://www.truemedmd.com

Link to this article

References

PCOS part three references

Estrogen Receptors altered in PCOS

1) http://www.medwirenews.com/45/12531/ObGyn/Estrogen_receptor_expression_altered_in_PCOS_follicles.html

Estrogen receptor expression altered in PCOS follicles
17 December 2002.  Journal of Clinical Endocrinology and Metabolism 2002; 87: 5532–8

The fertility problems associated with polycystic ovary syndrome (PCOS) may be partly due to abnormal granulosa cell expression of estrogen receptors (ERs) in women with the condition, a study shows.

Noting that high estrogen concentrations are “a defining characteristic of dominant follicles,” Dr. Denis Magoffin (Ceders-Sinai Medical Center, Los Angeles, California, USA) and co-investigators examined whether abnormal expression of ERs could contribute to poor follicular development and ovulatory failure in women with PCOS.

They obtained follicles from 12 polycystic ovaries from women with PCOS, and 23 normal ovaries from women with regular menstrual cycles.

Expression of ER-alpha mRNA was similar in control and PCOS follicles in the granulosa cells, but in the theca cells, ER-alpha concentrations were significantly increased in the PCOS samples, compared with the controls. ER-beta mRNA expression was higher in small antral than in dominant follicles from the control ovaries, and was observed at an intermediate level in PCOS follicles. Interestingly, however, ER-beta protein was detected at similar levels in the PCOS follicles and control dominant follicles.

“The results of this study demonstrate that there are significant alterations in the expression of ER-alpha and ER-beta in PCOS that may be related to abnormal follicular development,” Magoffin et al conclude.

Journal abstract

2) http://www.jbiomedsci.com/content/pdf/1423-0127-21-2.pdf  Endometrial progesterone resistance and PCOS.  Xin Li1,2, Yi Feng1,3, Jin-Fang Lin2  , Håkan Billig1 and Ruijin Shao

3) Ovarian Actions of Estrogen Receptor-β: An   Update  Ann E. Drummond, Ph.D.1 Peter J. Fuller, B.Med.Sci., M.B.B.S., Ph.D., F.R.A.C.P.1  1Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia Ovarian_Actions_of_Estrogen_Receptor_β_ Drummond_2012

4) http://www.ncbi.nlm.nih.gov/pubmed/19185861

Fertil Steril. 2010 Apr;93(6):1942-7. doi: 10.1016/j.fertnstert.2008.12.040. Epub 2009 Jan 30.
Estrogen receptor beta gene +1730 G/A polymorphism in women with polycystic ovary syndrome.  Kim JJ1, Choi YM, Choung SH, Yoon SH, Lee GH, Moon SY.
:
To investigate whether the +1730 G/A polymorphism in the estrogen receptor (ER)-beta gene is associated with susceptibility to polycystic ovary syndrome (PCOS).
DESIGN:

University Department of Obstetrics and Gynecology.
PATIENT(S): Women with (n = 138) or without (n = 290) PCOS.
INTERVENTION(S): Genotyping was performed by polymerase chain reaction-restriction fragment-length polymorphism analysis.
MAIN OUTCOME MEASURE(S): Genotype distribution and allele frequency of the +1730 G/A polymorphism in the ER-beta gene.
RESULT(S): There was a significant difference in the genotype distribution between the patients with PCOS and controls (non-GG rates were 22.1% for patients with PCOS and 36.6% for controls). There was also a significant difference in the G and A allele frequencies between these two groups (11.7% in patients vs. 19.1% in controls with A allele). But in patients with PCOS there were no significant differences in the serum levels of hormones, biochemical variables, or ovarian morphology between GG and non-GG genotypes.
CONCLUSION(S):

The ER-beta gene +1730 G/A polymorphism may be associated with pathophysiologic aberrancies involved in PCOS.

5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660316/
PLoS One. 2013; 8(5): e64801.  Published online May 21, 2013.doi:  10.1371/journal.pone.0064801

Genome-Wide Methylated DNA Immunoprecipitation Analysis of Patients with Polycystic Ovary Syndrome Hao-ran Shen,1 Li-hua Qiu,1 Zhi-qing Zhang,2 Yuan-yuan Qin,1 Cong Cao,2,* andWen Di1,*

Elevated Levels of BPA in PCOS

6) http://www.ncbi.nlm.nih.gov/pubmed/21193545
J Clin Endocrinol Metab. 2011 Mar;96(3):E480-4. doi: 10.1210/jc.2010-1658. Epub 2010 Dec 30.  Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS.  Kandaraki E1, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, Palimeri S, Panidis D, Diamanti-Kandarakis E.

Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbonate plastics. In experimental animals, neonatal exposure to BPA results in a polycystic ovary-like syndrome (PCOS) in adulthood. A bidirectional interaction between androgens and BPA levels has been disclosed.
OBJECTIVE:

To determine BPA levels in PCOS women as well as the association between BPA and hormonal/metabolic parameters compared to a control group.
DESIGN, SETTING, AND PARTICIPANTS:

Cross-sectional study of 71 PCOS (National Institutes of Health criteria) and 100 normal women, age- and body mass index-matched, in a University hospital setting.
MAIN OUTCOME MEASURES:

Anthropometric, hormonal, metabolic parameters and BPA blood levels were determined. Patients (PCOS) and controls (C) were further subdivided according to body mass index into lean and overweight subgroups, respectively.
RESULTS:

BPA levels were significantly higher in the total PCOS group compared with the controls (1.05±0.56 vs. 0.72±0.37 ng/ml, P < 0.001). PCOS women, lean (PCOS-L) and overweight (PCOS-OW), had higher BPA levels compared to the corresponding control group lean (C-L) and overweight (C-OW): (PCOS-L = 1.13±0.63 vs. C-L = 0.70±0.36, P < 0.001) (PCOS-OW = 0.96 ± 0.46 vs. C-OW = 0.72 ± 0.39, P < 0.05). A significant association of testosterone (r = 0.192, P < 0.05) and androstenedione (r = 0.257, P < 0.05) with BPA was observed. Multiple regression analysis for BPA showed significant correlation with the existence of PCOS (r = 0.497, P < 0.05). BPA was also positively correlated with insulin resistance (Matsuda index) in the PCOS group (r = 0.273, P < 0.05).
CONCLUSIONS:

Higher BPA levels in PCOS women compared to controls and a statistically significant positive association between androgens and BPA point to a potential role of this endocrine disruptor in PCOS pathophysiology.

7) Semin Reprod Med 2012; 30:32–38 .
Ovarian_Actions_of_Estrogen_Receptor_β_ Drummond_2012, Ph.D. 1 Peter J. Fuller, B.Med.Sci., M.B.B.S., Ph.D., F.R.A.C.P. 1 1 Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia

Polycystic Ovarian Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by anovulation, elevated levels of androgen, hirsutism, and insulin resistance.64,65 Folliculogenesis is arrested at the antral stage of development, and it is the accumulation of these follicles that gives the ovary its
characteristic morphology of a necklace-like pattern of follicles in the periphery. Because estrogen has been shown to be essential for folliculogenesis beyond the antral stage, it is perhaps not surprising that ERβ mRNA and protein are reduced in granulosa cells and theca cells from PCOS patients. 11,66

We hypothesized that changes in the ratio of ERβ το ERα may result in abnormal follicular development. Similarly, in a rodent model of PCOS, levels of ERβ protein were decreased in the granulosa layers of cystic follicles.67 Idiopathic ovulatory dysfunction has been found to be associated
with a G/A (1730) polymorphism in ERβ.2. Given that ovulatory dysfunction is a key feature of PCOS, one group investigated a cohort of PCOS patients to determine if there was an association with this polymorphism.68 They reported significant differences in the genotype distribution and allelic
frequencies between controls and PCOS patients that supported  a correlation with the G/A polymorphism.68 To date, the underlying mechanism has not been established.

8) Amir, Saira, et al. “Endocrine disruptors acting on estrogen and androgen pathways cause reproductive disorders through multiple mechanisms: a review.” International Journal of Environmental Research and Public Health 18.4 (2021): 1464.

EDCs can bind to estrogen receptors (ERα and ERβ) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.

It has been observed in recent years that fertility is declining at very high rates [25,26]. Decreased fertility rates in both men and women worldwide can be attributed to the increasing amounts of environmental toxicants [23,27,28].

9) Liu, Xiaohui, et al. “Bisphenol-C is the strongest bifunctional ERα-agonist and ERβ-antagonist due to magnified halogen bonding.” PloS one 16.2 (2021): e0246583.

We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ERα but as an antagonist for ERβ. Similar results were observed for bisphenol E analogs (BPE-X) such as BPE-F, BPE-Cl, and BPE-Br, each consisting of a series of a tri-halogenated methyl group CX3 in the central alkyl moiety. It was demonstrated that the electrostatic halogen bond based on the dispersion force of halogen atoms is a major driving force in the activities of bifunctional ERα-agonist and ERβ-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a π-π conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ERα-agonist and ERβ-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ERα and ERβ in the luciferase reporter gene assay using HeLa cells. With high receptor-binding ability to both ERs, BPC was found to be fully active for ERα but inactive for ERβ. BPC’s definite antagonist activity in ERβ was revealed by its inhibitory activity against 17β-estradiol. Thus, BPC is a bifunctional ERα-agonist and ERβ-antagonist. These agonist/antagonist activities were discovered to be extremely high among series of halogen-containing bisphenol compounds. This comparative structure-activity study revealed that the ascending order of ERα-agonist and ERβ-antagonist activities was BPE-F ≪ BPE-Cl ≲ BPAF < BPE-Br ≪ BPC. The highly intensified receptor interaction of BPC is attributable to the presence of an n-π-π-n conjugation system mediated through the >C = CCl2 double bond.

10) Markey, C., Luque, E., Munoz-de-Toro, M., Sonnenschein, C., & Soto, A. (2001). In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod, 65, 1215-1223.In utero exposure to bisphenol A alters development tissue organization of mouse mammary gland Markey Caroline M Biology of reproduction 2001

11) Jobling S, Reynolds T, White R, et al. (1995). A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ Health Perspect, 103:582-587.

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header image courtesy of Earth Times

BPA in every day products courtesy of Milwaukee Sentinel

BPA in plastics making us sick courtesy of  Health Environment Alliance

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
https://jeffreydachmd.com
http://www.drdach.com
http://www.naturalmedicine101.com
http://www.bioidenticalhormones101.com/
http://www.truemedmd.com

Last updated on July 29th, 2024 by Jeffrey Dach MD