Steroid hormones (estrogen and progesterone) play a major role in the etiology of breast cancer (8). An excess free serum estrogen level is responsible for the high rate of immature cell replication and increased fat metabolism in the body 12. The present study assessed the serum level of estradiol, progesterone, and lipid profile (TC, LDL-C, TG, and HDL-C) of the study participants. The biochemical parameters were compared between breast cancer patients and healthy controls by considering different associated factors such as sociodemographic characteristics, parity, menstrual phases, menopausal statuses, and BMI. The biochemical parameters of the study participants were also compared with normal reference ranges.
The results of this study showed that the mean serum progesterone levels were lower in breast cancer patients than in healthy controls in general and specifically with normal BMI, overweight, premenopause, and both menstrual phases. Previous studies done by Houghton et al., Hussain et al., and Kaaks et al., are in agreement with this study results 13–15. Saez et al. also proposed that a low progesterone /estrogen ratio and ovulatory cycles are more frequent in breast cancer patients than in a normal population and suggested that a relatively low progesterone secretion might favor the development of cancer 16. However, Ho et al., reported that in postmenopausal women serum progesterone levels were significantly associated positively with the chances of having breast cancer 17. On the contrary, Yu et al. did not find any significant difference in progesterone level between cancer patients and healthy controls of Chinese premenopausal women 18. In addition, Missmer et al. also reported no significant association between the breast cancer risk and the progesterone levels 19.
The reduction in progesterone level in the present study may be due to the ovarian hyperandrogenism hypothesis/ luteal inadequacy hypothesis, which states ovarian androgen excess, chronic anovulation, and an associated reduction of luteal phase progesterone production 15. The other reason could be due to a decrease in TG, LDL-C, and HDL-C concentrations in breast cancer patients. Because HDL-C and LDL-C may serve as the source of cholesterol in steroidogenesis 20. An additional justification is that the elevation level of estradiol can block ovulation, and may cause stress. Stress in turn increases the release of cortisol that decreases sex hormone-binding globulin (SHBG) and this leads to an increase in free estrogen level and decreased production of progesterone. The cortisol is responsible for the increase in the production of cortisol binding globulin that deactivates free progesterone in plasma by its binding activity 21.
Serum estradiol levels were insignificantly higher in breast cancer patients than that of healthy controls in general as well as for breast cancer risk factors, including age, BMI, menopausal statuses, and menstrual phases. These results are supported by the study results of Farhat et al., Trehan et al., and Blair 22–24. In contrast to the current study results, Hussain et al. stated that breast cancer patients showed a lower level of estrogen when compared with healthy controls 14. This could probably be due to the failure of proper matching between the cases and the controls concerning their different phases of the menstrual cycle during the measurements of the blood hormone. In addition, Abdelhadi reported no significant difference in the serum estrogen levels between the control subjects and the breast cancer patients of Sudanese women 25. Yu et al. and Awio et al. also suggested that there was no significant association between the estradiol level and breast cancer among Ugandan and Chinese women, respectively 18, 26. This contradiction may be due to the circulating levels of estrogen in premenopausal women, which is not only differ significantly from person to person but also vary substantially throughout the menstrual cycle. The less-stringent matching conditions on menstruation days may also hamper the ability to detect any significant difference in estrogen levels between the study groups.
The reason for the elevation of serum estradiol in the present study may be due to increased endogenous production of aromatase /overexpression of aromatase activity in extra ovarian tissues and within the tumor tissue 27–29. The other reasons may be the low concentration of SHBG that occurs in breast cancer patients, deficiency of vitamins like B, E, minerals like magnesium, and substance like indole 3-carbinol that may affect estrogen metabolism and increase free estrogen levels in the bloodstream 21.
The evaluation of serum lipid profile levels revealed that the mean serum TC levels were significantly lower in breast cancer patients compared with the healthy control group in general and particularly for the age category of 20-35 years and normal BMI. The results are in line with the study results of Li et al., Kshirsagar et al., Mishra, and Asegaonkar et al. 30–33. In contrast to our study results, Guan et al., Pandeya et al., Raza et al., Rohariya et al., and Nayak et al. indicated that an increase in TC levels was observed in breast cancer patients when compared to healthy controls 34–38. Interestingly, some studies reported TC levels were not significantly different between breast cancer patients and healthy control group 39–41.
The lowering of TC levels in breast cancer patients may be explained by the fact that there was a higher amount of estradiol and a lower amount of progesterone hormones in the serum of the breast cancer patients. The increased estradiol concentrations promote the activity of the hepatic triglyceride lipase (HTGL) enzyme and consequently decreases the synthesis of TC. The lowered concentrations of progesterone influence the action of estradiol on the lipid profile of the breast cancer patients 42. Perhaps, the enhancement of cholesterol utilization by neoplastic cells for new membrane biogenesis during cell proliferation might also have increased the catabolism of cholesterol and decreased cholesterol synthesis32. Another reason could be due to the lowering of progesterone concentration with excess androgenic effect on breast cancer patients.
The serum HDL-C levels were found to be significantly lower in breast cancer patients than in healthy controls. These phenomena were observed with the age category of 20-35 and above 45, normal BMI, and overweight, as well as at both menopausal statuses and follicular phase of the menstrual cycle. Our study results are supported by previously reported study results by Li et al., Kshirsagar et al., Pandeya et al., Raza et al., and Zhao et al. 30, 31, 35, 37, 39. Llanos et al. also reported that high levels of HDL-C were inversely associated with breast cancer among African-American women 43. In addition, Kshirsagar et al. revealed that low HDL-C levels may be associated with an increased risk of breast cancer 31. The decrease in HDL-C levels in breast cancer patients may be due to the lowering of serum TC level, because HDL–C may reverse transport of cholesterol 35. Although, maybe associated with lowering of progesterone in relation to excess androgenicity effect on breast cancer patients, that is associated with high levels of free biologically active estradiol. The consequences of excess estradiol level without controlling of progesterone decrease the LPL activity and reduce the production of HDL-C 9
Contrary to the above observations, Peela et al. reported significantly elevated serum HDL-C in breast cancer patients when compared to healthy controls 44. Martin et al. also found that the serum HDL-C was positively associated with a higher risk of breast cancer 40. On the other hand, the results of some researchers like Guan et al., Rohariya et al., Laisupasin et al., and Abdelsalam, et al. indicated that there were no significant differences between HDL-C levels between breast cancer patients and healthy control group 34, 36, 45, 46. Concerning the TG and LDL-C levels, no significant difference was observed between the breast cancer patients and healthy controls.
In the current study, the assessment of abnormality of mean serum estradiol, progesterone, and lipid profile levels of breast cancer patients and healthy controls was compared with reference range /cut off points. Accordingly, in breast cancer patients, except TC and LDL-C, the levels of measured parameters showed higher abnormality compared to reference range /cut off points. Markedly, 62.5% and 72.5% of the breast cancer patients exhibited lower progesterone and HDL-C levels, respectively compared to cut-off points. All of the 62.5% progesterone abnormality in breast cancer patients was observed in premenopause. Our results are supported by Flote et al. 47. The main reason for the abnormality of progesterone may be due to estrogen (estradiol) dominance in breast cancer patients (21). Another justification could be the ovarian hyperandrogenism hypothesis associated reduction of luteal phase progesterone production 15 excess estradiol may leads to lower serum TC, LDL-C and HDL-C which required for production of progesterone 20. In addition, estrogen-induced cortisol levels can decrease sex hormone binding-globulin and increase corticosteroid-binding globulin, which leads to progesterone deactivation 21. The possible mechanisms responsible for the abnormality of HDL-C level in breast cancer patients could be; i. the reduction of TC level as the result of an increase in neoplastic transformation of the cancer cells 35, 41; ii .inactivation of the lipolytic enzymes (lipoprotein lipase and hepatic lipoprotein lipase) 9,48 and iii. the absence of sufficient quantities of progesterone that can lead the body to make androgens to regulate the effect of estrogen 42.