Effect of Hyperinsulinaemia and Insulin Resistance on Endocrine, Metabolic and Fertility Outcomes in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction

Duojia Zhang; Xinming Yang; Jian Li; Jiarui Yu; Xiaoke Wu

Disclosures

Clin Endocrinol. 2019;91(3):440-448. 

In This Article

Discussion

The data in this study came from a large-scale survey of a hospital-based cohort of women with PCOS across China. We defined Chinese PCOS patients by the 'modified Rotterdam Diagnostic Criteria', which was developed by the Gynecological Endocrinology Group of the Chinese Medical Association in 2011 with the support of the Ministry of Health of China.[13] We evaluated the association between hyperinsulinaemia and IR and phenotypic features of women with PCOS, including circulating sex steroids, glucose and lipid metabolism, metabolic syndrome and fertility outcomes.

Our results showed that increased FIN and HOMA-IR were strongly associated with exacerbation of PCOS phenotypes, including weight, waist and hip circumference, BMI, WHR and acanthosis nigricans score. Our results were consistent with previous reports[18] suggesting that obesity and IR are reciprocal. The waist circumference and WHR partly reflect the distribution of body fat. The increase in abdominal fat releases a large number of free fatty acids, adipokines and cytokines that are closely related to IR.[19,20] We did not find any correlation between the hirsutism score or acne score with FIN or HOMA-IR. A recent study[21] found that HOMA-IR was positively associated with FG score after adjustments for age, BMI, TT and the number of menses per year. However, another previous study[22] found there was no difference in insulin sensitivity between hirsute and nonhirsute women, and normal weight and overweight women with hirsutism can have normal insulin sensitivity and normal levels of circulating androgens. We think this is likely because the severity of hirsutism or acne does not necessarily correlate with circulating androgen levels and instead depends on both individual reactions of pilosebaceous units to androgens[23] and the androgen receptor activity in the pilosebaceous units.[24]

Furthermore, we analysed the correlation between circulating sex steroids and gonadotrophins and FIN and HOMA-IR and found significant negative associations for SHBG with FIN and HOMA-IR and significant positive associations for FAI. Insulin can affect the expression of androgens by suppressing concentrations of SHBG, and decreased SHBG secretion is considered a marker of both IR and hyperandrogenaemia. FAI is an indicator for the level of testosterone after adjusting for abnormal SHBG and reflects not only the level of FT, but also the level of IR. Studies have shown that there is no overlap in FAI between PCOS patients and non-PCOS patients,[25] and the results of the present study showed that FIN and HOMA-IR were positively correlated with FAI levels. Androgen levels in adults decline steeply with age,[26] and after adjusting for age, we found that serum insulin levels were positively correlated with circulating FT levels suggesting that insulin contributes to hyperandrogenism in PCOS. Some previous studies have shown that circulating concentrations of insulin are positively associated with androgen level,[27] but other studies have not found a correlation between insulin and androgen levels.[28] Insulin inhibits the synthesis of insulin-like growth factor (IGF) binding globulin-1 in the liver[29] resulting in an increase in free IGF-1, and insulin and IGF-1[30,31] work synergistically with LH-stimulated ovarian androgen synthesis in theca interstitial cells. In addition, insulin augments the 17-hydroxylase activity of P450c17, an enzyme involved in the regulation of androgen synthesis, and thus insulin directly promotes the production of ovarian androgen.[32] Our study found no correlation between the levels of LH or LH/FSH with FIN or HOMA-IR after adjusting for the influence of BMI. There is evidence that obesity has a negative effect on the increase in GnRH-LH impulsive secretion, and the impulse amplitude of GnRH/LH decreases in obese women with PCOS, while the level of LH increases only slightly or not at all.[33] We found that prolonged menstrual period was significantly and positively correlated with FIN and HOMA-IR, but PCOM was not related to insulin level or IR. This illustrates that hyperinsulinaemia mainly interferes with follicular development and causes ovulation dysfunction.

When correlating insulin level and IR with PCOS metabolic profiles, we found that metabolic indexes of PCOS such as cholesterol, TG, LDL and Apo B were significantly and positively associated with FIN and HOMA-IR, while HDL was negatively associated. These results confirm those of previous reports.[8] IR and hyperinsulinaemia can promote liver secretion of very-low-density lipoprotein (VLDL) and active hepatic endothelial lipase that promotes HDL decomposition and decreasing HDL-c concentration.[34] Insulin also inhibits the activation of TG lipase (a key rate-limiting enzyme for lipid mobilization), resulting in increased lipid mobilization and TG synthesis.[35] IR is an early risk indicator of metabolic syndrome, and this study found that the incidence of metabolic syndrome is closely associated with the level of FIN and HOMA-IR.

This study was a predictive study of hyperinsulinaemia and IR on fertility outcome. We found that with increasing serum insulin level and the aggravation of IR, the rates of ovulation, conception, pregnancy and live birth significantly decreased. After adjustments for age, total testosterone and free testosterone, increasing serum insulin levels and HOMA-IR were significantly associated with decreased cycle ovulation, conception, pregnancy and live birth rates. This indicates that hyperinsulinaemia and IR can lead to declining fertility. A possible reason for this is that hyperinsulinaemia and IR lead to follicular dysplasia, resulting in the decline of follicular quality, inadequate luteal function and progesterone hyposecretion, all of which negatively affect fertility. Insulin and IGF-1 and IGF-2 play pivotal roles in the proliferation of granulosa cells and thus are important for the growth and development of follicles.[36] The high levels of insulin seen in PCOS patients result in an increase in free IGF-1 levels,[29] whereas the reduction of free IGF-2 in the follicular fluid is similar to that in normal ovulatory women with atretic follicles, which cannot amplify granulosa cell proliferation and E2 production in response to FSH.[37] A high level of free IGF-I will downregulate the expression of IGF-I receptors, which promote glucose uptake through glucose transporter channels, and thus when IGF-I receptors are down-regulated glucose uptake is impaired.[38] In addition, increased free IGF-I can synergize with high LH to increase the premature overexpression of LH receptor in the theca interna and negatively affect follicular development, thus leading to cell proliferation in the theca interna and thickening of the theca folliculi.[31] It has been shown[39] that the local hyperinsulinaemic environment of the ovary has a significant effect on glucose utilization in granulosa cells, and it has thus been inferred that hyperinsulinaemia might affect the utilization of glucose by reducing the rate of glycolysis in follicles and thereby reducing the energy supply in follicles and slowing their growth. Follicular hyperinsulinaemia promotes androgen biosynthesis in the follicles, and this might impair communication between granulosa cells[40] and inhibit FSH-induced aromatase activity[41] and impair the development of dominant follicles. The growth of antral follicles is blocked in PCOS patients with IR,[42] and IR leads to poor outcomes in IVF and ICSI[43] and in laparoscopic ovarian diathermy[44] in these women. Previous research has also shown that reducing insulin resistance can improve ovulation and restore ovulatory menstrual cycles.[45]

This article was an exploratory study on the relationship between FIN and HOMA-IR and baseline parameters and outcomes of infertility treatment in PCOS patients. We show that hyperinsulinaemia and IR can aggravate the phenotypic characteristics, reproductive endocrine disorders (FT and FAI), and glucose and lipid metabolic dysfunction in PCOS patients and thus lead to reduced fertility in these women. Thus, reducing IR in PCOS patients is of great significance in restoring ovarian function, improving clinical symptoms, increasing fertility and reducing long-term complications.

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