The correlation of aromatase activity and obesity in women with or without polycystic ovary syndrome
- Jie Chen†1, 2,
- Shanmei Shen†3,
- Yong Tan1Email author,
- Dong Xia2,
- Yanjie Xia2,
- Yunxia Cao4,
- Wenjun Wang5,
- Xiaoke Wu6,
- Hongwei Wang2,
- Long Yi2,
- Qian Gao2 and
- Yong Wang2Email author
© Chen et al.; licensee BioMed Central. 2015
Received: 18 September 2014
Accepted: 6 March 2015
Published: 22 March 2015
This study aimed to investigate the effect of polycystic ovary syndrome (PCOS) on the association of aromatase activity assessed by estradiol-to-testosterone ratio (E2/T) with body mass index (BMI) in women.
This was a cohort study in five centers for reproductive medicine in China. Data were collected from July 2012 to December 2013. PCOS patients (n = 785) and non PCOS, healthy, age-matched controls (n = 297) were included. Plasma sex hormones including estradiol (E2), testosterone (T), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were measured by ELISA, together with BMI and E2/T being calculated, on the third day of the menstrual cycle. Aromatase activity in PCOS patients with different BMI, T and E2 levels were compared.
E2/T was significantly lower (P < 0.05) while BMI was significantly increased (P < 0.05) in PCOS than non-PCOS. No significant difference was observed in E2/T among different BMI subgroups of either PCOS or control. Ovarian aromatase activity was decreased in PCOS patients which was independent of BMI. Hyperestrogen promoted ovarian aromatase activity, while hyperandrogen inhibited such activity, both in a dose-dependent, biphasic manner.
Ovarian aromatase activity was lower in PCOS, which was independent of BMI. New therapeutic strategies can be developed by targeting aromatase activity for treating PCOS women, especially those with obesity.
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by dysfunction of gonadal axis and systemic nerve endocrine metabolic network , with a prevalence of up to 10% in women of reproductive age [2,3]. Furthermore, this number may underestimate the severity of the situation as many women with PCOS in the community remain undiagnosed . PCOS has significant and diverse clinical implications including reproductive, endocrine and metabolic abnormalities such as hyperandrogenism and obesity . Obesity, particularly abdominal obesity, is one of the independent factors aggravating the PCOS endocrine disorders, as subcutaneous abdominal adipose tissues and the liver tissues contribute to extragonadal aromatization .
Aromatase, a product of the CYP19 gene , is a member of the cytochrome P450 family . Aromatase is a rate-limiting enzyme that catalyzes the conversion of androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) during steroidogenesis . In ovaries, estradiol is generated by converting C19 androgens derived from theca cells under the influence of aromatase produced by granulosa cells . Consequently, the ratio of estradiol (E2) to testosterone (T) has been used to evaluate aromatase activity [10,11]. Multiple studies have reported a dysfunctional P450-aromatase activity in PCOS women. However, whether the abnormality is caused by hyperfunction or insufficiency of the enzyme remains unknown [12-16]. The nature of the interaction between ovarian aromatase activity and PCOS in women has been controversial, and the impact of weight gain on aromatase activity as well as E2 levels is unknown.
The objective of this study was to investigate the association and interaction between aromatase activity and levels of body mass index (BMI) from a reproductive hormone perspective in a group of women with or without PCOS.
We designed a cohort study which included 1082 individuals from five clinical centers (785 PCOS and 297 age-matched non-PCOS) from July 2012 to December 2013. The study was approved by the Medical Ethics Committee of the Medical School of Nanjing University, Nanjing, China.
Inclusion and exclusion criteria
PCOS was diagnosed according to the 2006 Rotterdam criteria . PCOS may be confirmed if any two out of the following three criteria are met and any other diseases that cause anovulation or hyperandrogenism can be excluded: (1) Oligovulation or anovulation, (2) Clinical manifestation or biochemical evidence of hyperandrogenism, (3) Occurrence of PCO (at least 12 antral follicles measuring 2–9 mm in diameter or the enlargement of an ovarian volume to more than 10 ml by transvaginal ultrasound). The non-PCOS women were selected from infertile couples if the infertility was attributed to male factors in the study period. All the subjects were between 20 and 35 years of age who had not been taking hormone drugs such as contraceptives, ovulation drugs, corticosteroids three months prior to inclusion and who did not have serious heart, liver, renal, and hematopoietic system diseases or malignant tumors.
Controls were recruited from healthy women with a regular menstrual cycle, normal basal sex hormones levels and absence of PCO on sonography.
Clinical and hormonal analyses
BMI was calculated as weight in kilograms divided by the square of height in metres (kg/m2). Peripheral blood samples were taken between 08:00–09:00 A.M. on the third day of the menstrual cycle from all subjects after overnight fasting and frozen at −80°C until assayed. Sex hormones including E2, T, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured by ELISA (Beijing North Institute of Biological Technology of China and the CIS Company of France). Intra- and inter-assay coefficients of variation were 10% for all the assays.
Both the PCOS patients and non-PCOS subjects were allocated to one of the three subgroups, namely the obese subgroup (BMI ≥ 23 kg/m2), the normal-weight subgroup (18.5 kg/m2 ≤ BMI < 23 kg/m2) and the underweight subgroup (BMI < 18.5 kg/m2), based on WHO recommendations for the Asia-Pacific region .
PCOS patients were also divided into subgroups based on the levels of T (T ≥ 2.44 nmol/L or T < 2.44 nmol/L) and E2 levels (E2 > 293.6 pmol/L, 146.8 ≤ E2 ≤ 293.6 pmol/L, or E2 < 146.8 pmol/L). The cuts-off were defined by normal laboratory reference values of reproductive medicine centers.
SAS version 9.0 (USA) software was used to match cases and controls based on age. SPSS version 17 (SPSS, Chicago, IL, USA) was used to process the data. Parameters were described using mean ± standard deviation, or median ± quartiles (for data not normally distributed) and the statistical analyses were carried out by t-test and the rank-sum test, respectively. Subgroup differences were calculated by single-factor ANOVA. P < 0.05 was considered statistically significant.
Aromatase activity in PCOS
Biochemical data from PCOS and non-PCOS groups
P (n = 785)
non P (n = 297)
23.87 ± 4.85a
22.30 ± 3.27
254.81 ± 169.20a
219.73 ± 166.32
2.60 ± 1.58a
1.20 ± 0.70
5.98 ± 2.93a
6.43 ± 2.17
11.90 ± 8.31a
5.37 ± 3.80
Aromatase activity in women with different BMI with or without PCOS
Biochemical data of the subjects by BMI
BMI ≥ 23 kg/m 2
18.5 kg/m 2 ≤ BMI < 23 kg/m 2
BMI < 18.5 kg/m 2
P (n = 388)
Non P (n = 103)
P (n = 343)
Non P (n = 174)
P (n = 54)
Non P (n = 20)
27.46 ± 4.39a,b,d
25.86 ± 2.66a,b
20.79 ± 1.24c
20.73 ± 1.23c
17.54 ± 0.87
17.67 ± 0.95
247.95 ± 161.61d
213.98 ± 164.51
258.49 ± 174.83d
222.07 ± 166.43
280.72 ± 185.52
228.93 ± 182.02
2.60 ± 1.66d
1.23 ± 0.64b
2.57 ± 1.45d
1.21 ± 0.74c
2.81 ± 1.80d
0.86 ± 0.53
5.74 ± 2.80a,d
6.40 ± 2.47
6.19 ± 2.79d
6.44 ± 2.06
6.40 ± 4.29
6.50 ± 1.46
10.16 ± 7.24a,b,d
5.22 ± 3.82
13.24 ± 8.94b,d
5.39 ± 3.75
15.90 ± 8.52d
5.98 ± 4.15
Aromatase activity in PCOS patients with different E2 levels
Biochemical data of PCOS patients by E 2 levels
P (n = 785)
E 2 > 293.6 pmol/L (n = 233)
146.8 ≤ E 2 ≤ 293.6 pmol/L (n = 348)
E 2 < 146.8 pmol/L (n = 204)
23.32 ± 4.58b
23.92 ± 4.90
24.40 ± 5.03
455.73 ± 169.42a,b
212.23 ± 40.01c
97.96 ± 29.27
2.97 ± 1.53a,b
2.59 ± 1.55c
2.19 ± 1.59
5.64 ± 3.60a
6.21 ± 2.55
5.97 ± 2.63
12.76 ± 9.97b
12.12 ± 7.30c
10.55 ± 7.71
Aromatase activity in PCOS patients with different T levels
Biochemical data of the PCOS patients by T levels
P (n = 785)
T ≥ 2.44 nmol/L (n = 364)
T < 2.44 nmol/L (n = 421)
23.35 ± 4.16
24.31 ± 5.34
289.41 ± 179.69a
224.89 ± 153.62
3.85 ± 1.46a
1.52 ± 0.55
6.29 ± 2.84a
5.71 ± 2.98
14.03 ± 9.03a
10.06 ± 7.15
The human aromatase gene contains 10 exons and one of them encodes nine alternative promoters to regulate tissue-specific expression, and the other nine are the protein-coding exons . Aromatase is expressed in specific cell populations of a variety of estrogen-producing tissues, including placenta, ovaries, testes, skin, adipose tissue, bone, brain, and vascular smooth muscle cells . Importantly, aromatase in ovarian granulosa and luteinized granulosa cells plays an important role for women of reproductive age.
In this study, we aimed to discover the association between aromatase activity, obesity and sex hormones in a large, well-described cohort of PCOS patients. However, there is certain controversy regarding the correlation of ovarian aromatase activity with PCOS . The E2/T ratio provides important information about aromatase activity because conversion of androgens to estrogens is mediated by CYP19, suggesting that the E2/T ratio may be a direct marker of aromatase activity . Based on our data, PCOS is manifested by a typical abnormal hormone pattern where the increase of LH, testosterone, and estradiol is accompanied with reduced levels of FSH, FSH/LH, and E2/T. We found a significant decrease of ovarian aromatase activity in women with PCOS as compared to controls which is consistent with previous work [8,16,21]. In the polycystic ovary, theca cells synthesize more androgens than the corresponding cells in a normal ovary. In contrast, granulosa cells in the polycystic ovary have a lower aromatase activity, which results in an imbalance in the production of estrogen and androgen. An earlier research by Soderlund and co-workers found no gross deletions or insertions after PCR amplification of the nine exons of the P450 arom gene from the peripheral blood leukocytes of 25 PCOS patients . But this cannot preclude the importance of an aromatase disorder in the etiology of PCOS, as there may exist causative mutations in the untranslated regions or within introns.
There is evidence that obesity, particularly abdominal obesity, exacerbates both the clinical and endocrine features of PCOS  which demonstrates significantly more serious insulin resistance in these individuals than normal-weight counterparts . Although obesity is not included in the diagnostic criteria for PCOS, 35% to 80% of PCOS women, depending on the setting of the study and the ethnic characteristics of the patients, are commonly overweight (BMI above 25 kg/m2) or obese (BMI above 30 kg/m2) . Our findings associated higher BMI with PCOS but no concomitant change of E2/T was observed. It is reported that estrogen has the capacity to favorably regulate body composition and glucose homeostasis to prevent diet-induced obesity .
Aromatase expression in the ovarian follicle is also responsible for the cyclic changes in serum estradiol levels and the modulation of the structure and function of the female reproductive tract and is essential for the survival, fertilization and implantation of oocytes. PCOS promotes a hyperestrogenic state. In this research, PCOS with high estradiol levels led to more serious hyperandrogenism but with relatively elevated levels of E2/T. This is consistent with a previous study showing that higher estradiol levels are caused by increased RNA expression of granulosa cell aromatase and its activity .
Nevertheless, high testosterone levels of PCOS inhibited aromatase activity. We hypothesize that androgen can dose-dependently affect aromatase activity directly, or indirectly by regulating other factors such as E2 and LH. One report suggests that early exposure of females to androgen induces sex-specific organizational changes of aromatase expression in the preoptic area .
Hyperinsulinemia and insulin resistance play a role in the pathogenesis of PCOS. Analyzing existing studies, the relationship between insulin and activity of cytochrome P450 family has been explored. La Marca gave a direct demonstration that decreasing insulin with metformin led to a reduction in stimulated ovarian P450c17α activity in PCOS and Nestler JE’s study showed the similar result in lean PCOS [29,30]. Whether P450 aromatase activity may be dependent on insulin resistance will be investigated in our follow-up work.
PCOS is a common ovulatory disorder in young women, which affects 5-10% of the population and results in infertility due to anovulation . Although the pathogenesis of PCOS is still unclear, the role of hyperandrogenism in the pathophysiology of PCOS has been established but not clearly. Oral contraceptives, such as ethinylestradiol and cyproterone acetate tablets, drospirenone and ethinylestradiol tablets, have been used in the clinic to reduce hyperandrogen and to suppress follicular development. Letrozole, an aromatase inhibitor, can induce ovulation in PCOS so that a normal serum androgen level can be maintained by blocking the early low estrogen negative feedback. Generation and metabolism of androgen is directly related to aromatase activity. Along this line, aromatase-agonist-like-drugs perhaps can directly induce follicular development and shorten the treatment course of PCOS women irrespective of the original hyperandrogen state.
We checked controls for PCOS features (PCOM, hyperandrogenism, oligo-anovulation) in this study. Testosterone was the only androgen that was measured in our study and other androgens such as androstenedione and dehydroepiandrosterone sulfate do not be analyzed because of the limitation of research funding.
Taken together, our results showed that ovarian aromatase activity in PCOS was decreased which was independent of BMI. Hyperestrogen promoted ovarian aromatase activity which could be inhibited by hyperandrogenism in a dose-dependent manner demonstrating a complex biphasic correlation.
In both normal women and PCOS patients, estrogen levels negatively correlated to BMI. Aromatase, the master convertor of androgen to estrogen, can regulate the estradiol-to-testosterone ratio and thereby regulates BMI. Thus, enhancing aromatase activity may become an optimized strategy for developing therapies for PCOS women, especially those with obesity.
We would like to extend our sincere thanks to all those who participated in the study, especially those healthy controls.
This study was supported by the National Natural Science Foundation of China (814714222, 81373683, 81170541), Science and Technology Project of Jiangsu Province of China (SBL201320056), the Ph.D. Program Foundation of the Ministry of Education of China (20123237110004) and the Ordinary University Graduate Practice Innovation Plan of Jiangsu Province, China (SJZZ_0123).
- Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lob R. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97:28–38.View ArticlePubMedGoogle Scholar
- Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18:671–83.View ArticlePubMedGoogle Scholar
- Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7:219–31.View ArticlePubMedGoogle Scholar
- March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25:544–51.View ArticlePubMedGoogle Scholar
- Cupisti S, Kajaia N, Dittrich R, Duezenli H, Beckmann MW, Mueller A. Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome. Eur J Endocrinol. 2008;158:711–9.View ArticlePubMedGoogle Scholar
- Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L. Human aromatase: gene resequencing and functional genomics. Cancer Res. 2005;65:11071–82.View ArticlePubMedGoogle Scholar
- Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene:update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol. 2003;86:219–24.View ArticlePubMedGoogle Scholar
- Lesley J, Millsa, Ruth E, Gutjahr G, Gerald E, Zaroogiana, et al. Modulation of aromatase activity as a mode of action for endocrine disrupting chemicals in a marine fish. Aquat Toxicol. 2014;147:140–50.View ArticleGoogle Scholar
- Leandros L, Nectaria X, Elissavet H, Atsushi T, Apostolos K, Georgios M, et al. CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovary syndrome. Gynecol Endocrinol. 2013;29:478–82.View ArticleGoogle Scholar
- Jiang J, Tang NL, Ohlsson C, Eriksson AL, Vandenon Put L, Chan FW, et al. Association of genetic variations in aromatase gene with serum estrogen and estrogen/testosterone ratio in Chinese elderly men. J Clin Chim Acta. 2010;411:53–8.View ArticleGoogle Scholar
- Jakimiuk AJ, Weitsman SR, Brzechffa PR, Magoffin DA. Aromatase mRNA expression in individual follicles from polycystic ovaries. Mol Hum Reprod. 1998;4:1–8.View ArticlePubMedGoogle Scholar
- Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med. 1989;320:559–65.View ArticlePubMedGoogle Scholar
- Suikkari AM, McLachlan V, Montalto J, Calderon I, Healy DL, McLachlan RI. Ultrasonographic appearance of polycystic ovaries is associated with exaggerated ovarian androgen and estradiol responses to gonadotrophin-releasing hormone agonist in women undergoing assisted reproduction treatment. Hum Reprod. 1995;10:513–9.PubMedGoogle Scholar
- Ibanez L, Hall JE, Potau N, Carrascosa A, Prat N, Taylor AE. Ovarian 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation testing. J Clin Endocrinol Metab. 1996;81:4103–7.PubMedGoogle Scholar
- Fulghesu AM, Villa P, Pavone V, Guido M, Apa R, Caruso A, et al. The impact of insulin secretion on the ovarian response to exogenous gonadotropins in polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:644–8.View ArticlePubMedGoogle Scholar
- Ia Marca A, Morgante G, Palumbo M, Cianci A, Petraglia F, De Leo V. Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78:1234–9.View ArticleGoogle Scholar
- Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.Google Scholar
- International Diabetes Institute World Health Organization, West Pacific Region. The Asia Pacific Perspective: redefining obesity and its Treatment. In: International Association for the Study of Obesity and International Obesity Task Force. 2000.Google Scholar
- Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease:from bench to treatment. Pharmacol Rev. 2005;57:359–83.View ArticlePubMedGoogle Scholar
- Jin JL, Sun J, Ge HJ, Cao YX, Wu XK, Liang FJ, et al. Association between CYP19 gene SNP rs2414096 polymorphism and polycystic ovary syndrome in Chinese women. BMC Med Genet. 2009;10:139.View ArticlePubMed CentralPubMedGoogle Scholar
- Kirilovas D, Chaika A, Bergström M, Bergstrom-Petterman E, Carlström K, Nosenko J, et al. Granulosa cell aromatase enzyme activity: effects of follicular fluid from patients with polycystic ovary syndrome, using aromatase conversion and [11C]vorozole-binding assays. Gynecol Endocrinol. 2006;22:685–91.View ArticlePubMedGoogle Scholar
- Soderlund D, Canto P, Carranza-Lira S, Mendez JP. No evidence of mutations in the P450 aromatase gene in patients with polycystic ovary syndrome. Hum Reprod. 2005;20:965–9.View ArticlePubMedGoogle Scholar
- Kaya C, Cengiz SD, Satiroglu H. Obesity and insulin resistance associated with lower plasma vitamin B12 in PCOS. Reprod Biomed Online. 2009;19:721–6.View ArticlePubMedGoogle Scholar
- Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab. 1996;81:2854–64.PubMedGoogle Scholar
- Hahn S, Tan S, Sack S, Kimmig R, Quadbeck B, Mann K, et al. Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2007;115:130–5.View ArticlePubMedGoogle Scholar
- Barrera J, Chambliss KL, Ahmed M, Tanigaki K, Thompson B, McDonald JG, et al. Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis and type 2 diabetes in mice without impacting the reproductive tract. Am J Physiol Endocrinol Metab. 2014;307:E345-54.Google Scholar
- Shaw ND, Srouji SS, Welt CK, Cox KH, Fox JH, Adams JM, et al. Evidence that increased ovarian aromatase activity and expression account for higher estradiol levels in African American compared with Caucasian women. J Clin Endocrinol Metab. 2014;99:1384–92.View ArticlePubMed CentralPubMedGoogle Scholar
- Gonzalez B, Ratner LD, Scerbo MJ, Di Giorgio NP, Poutanen M, Huhtaniemi IT, et al. Elevated hypothalamic aromatization at the onset of precocious puberty in transgenic female mice hypersecreting human chorionic gonadotropin: effect of androgens. Mol Cell Endocrinol. 2014;390:102–11.View ArticlePubMedGoogle Scholar
- La Marca A, Egbe TO, Morgante G, Paglia T, Cianci A, De Leo V. Metformin treatment reduces ovarian cytochrome P-450c17alpha response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome. Hum Reprod. 2000;5:21–3.View ArticleGoogle Scholar
- Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82:4075–9.PubMedGoogle Scholar
- Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;85:2434–8.PubMedGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.