Type 2 diabetes mellitus (T2DM) is a common disease with a serious global pandemic, and could cause substantial adverse impacts on human health (1). The dramatically rising global prevalence of T2DM especially in young adults further increases its global burden (2). Apart from those common diabetic complications such as diabetic neuropathy and diabetic retinopathy, reproductive dysfunction or complications such as subfertility are also prevalent in diabetic patients (3). Ovarian aging commonly refers to the decline of female ovarian functions with age, accompanied by the deterioration in the quantity and quality of ovarian follicles, and dysfunction of granulosa cells and theca cells. (4, 5) Some previous studies have found an association between type 1 diabetes mellitus and accelerated ovarian aging (6–8), and a few studies based on animal models demonstrate that diabetes-obesity syndrome may be associated with impaired oocyte quality (9, 10). However, clinical research on the association between T2DM and accelerated ovarian aging is limited, and the results have been inconsistent. Some studies reported accelerated ovarian aging in patients with T2DM (11–13) while others found no relationships between T2DM and reproductive aging (8, 14).

Cardiovascular complications and microvascular complications are common in patients with T2DM (15, 16). Cardiovascular disease (CVD) is the leading cause of mortality in postmenopausal women (17, 18), and the morbidity rate of CVDs in DM patients is more than twice of that of non-diabetic patients (19). As one of the major causes of atherosclerotic cardiovascular diseases, the dysregulation of lipid metabolism serves as a common feature of T2DM, traditionally characterized by elevated fasting and postprandial triglycerides (TC), low high density lipoprotein-cholesterol (HDL-C), high low density lipoprotein-cholesterol (LDL-C) (20–22). As one of the major characteristics of dyslipdemia, increased LDL-C is an independent risk factor for the development of CVDs, which in women usually occurs in the postmenopausal state (23–25). Among sex hormones, negative associations of E2 with TC and LDL-C have been demonstrated in estrogen receptor (ERα) -deficient models, postmenopausal women with E2 deficiency and women on E2 treatment (26–28). However, studies on the relations between gonadotropins– luteinizing hormone (LH) and follicle-stimulating hormone (FSH)– and lipid levels are still limited and have reported inconsistent findings (27, 29–31). For instance, emerging evidence indicates that FSH level may relate to CVD risks through its association with lipid levels, and some observational studies on women in the menopausal transition demonstrates the association positive (32–35), while other studies on postmenopausal women and older postmenopausal women show it negative (18, 30, 31). Furthermore, clinical investigations show that adoption of hormone replacement therapy (HRT) based on E2 level alone only partially reversed dyslipidemia or lipid oxidation in postmenopausal women. These lead us to hypothesize that gonadotropins may have independent impacts on the lipid profile in perimenopausal or postmenopausal women with T2DM.

The primary purpose of this study is to assess the differences in the age-specific trends of sex hormones in female patients with T2DM and non-T2DM controls, thereby evaluating accelerated ovarian aging in women with T2DM; we also aim to study the correlations of sex hormones with the lipid profile among patients with T2DM.

A major finding in this study is the accelerated ovarian aging among patients with T2DM. Reproductive aging such as premature ovarian failure can promote the development of cardiovascular diseases and has been reported among patients with T1DM (6–8). However, the reproductive aging of patients with T2DM is less well understood, and evidence from clinical studies is still limited. In the present study, we found that LH and FSH both started to increase obviously approximately from the age of 45 years among patients with T2DM, and displayed peaks of LH and FSH among patients with T2DM aged between 61 and 65, both of which were obviously earlier than that in non-T2DM controls; meanwhile, E2 started to decrease obviously approximately from the age of 40 years among patients with T2DM, while it started to decrease obviously approximately from the age of 45 years among non-T2DM controls (Figure 2). The findings above prove that aging-related changes in sex hormones occur earlier in patients with T2DM and patients with T2DM have accelerated ovarian aging than controls.

The age-specific trends of LH, FSH and E2 in patients with T2DM and non-diabetic controls are consistent with findings from several studies (11–13). Previous clinical research found a decline in ovarian volume, total antral follicle count, inhibin B secretion and anti-Miller hormone level in patients with T2DM compared with healthy controls, all of which were also markers for ovarian aging (9, 43). And a few studies based on animal models demonstrated that diabetes-obesity syndrome was associated with suppression of cyclic ovarian follicular recruitment patterns, anovulation, acyclicity, depressed ovarian steroid hormone synthesis and release, hypovascularization and tissue ischemia, enhanced follicular atresia, premature tissue atrophy and involution (9, 10). Despite such supporting evidence for accelerated ovarian aging in patients with T2DM, the underlying mechanisms are far from being clarified. Here, we deduced several possible mechanisms as follows: 1) It’s well established that low-grade chronic inflammation is involved in the pathophysiology T2DM (44), due mainly to the activation of the myeloid cell lineage (e.g., macrophages and neutrophils) (45). Inflammation of the whole body can affect oocytes via the follicle microenvironment and oxidative stress (46), thus impairing oocyte meiosis and oocyte quality (47). Indeed, chronic inflammation is found in aging ovaries, which is proved by the increase of multiple proinflammatory transcription factors, cytokines and chemokines (4, 48). For example, TNF-α binds to its death receptors (such as Fas) and then activates apoptosis of granular cells and oocytes through Fas-associated death domain-dependent activation of caspase-8; while TNFα knockout mice proved higher levels of granular cell proliferation (49). In addition, macrophage infiltration could induce the accumulation of collagen fibers in extracellular matrix, thereby promoting ovarian fibrosis (50). 2) Oxidative stress plays a key role in the pathophysiology of T2DM. During the progression of diabetes, hyperglycemia promotes mitochondrial dysfunction and induces the formation of oxygen species (ROS) that causes oxidative stress in several tissues including ovaries (45). And several studies have shown that the accumulation of ROS in the ovaries deteriorates oocyte quality, induces granulosa cell apoptosis, and accelerates degeneration of the corpus luteum (51). Excessive ROS may change the mitochondrial membrane potential by regulating the ratio of pro-/anti-apoptosis factors (49, 52), which eventually leads to the activation of caspase-3 which cleaves various structural and regulatory proteins in ovarian cells and causes apoptosis (46, 49). Moreover, oxidative stress and the accumulation of acquired mtDNA mutations could cause mtDNA damage (53). The effect of mtDNA alterations in ovarian follicle cells on qualitative ovarian reserve depletion and ovarian aging is also supported by the robust evidence (46, 53), though the mechanisms require further probe. 3) Vascular damage is one of the most common complications of diabetes, characterized by endothelium cell dysfunction, impaired angiogenesis, platelet activation and subsequent microembolisms (45). According to previous research, vascular impairment could lead to early menopause (54), in which the pathophysiological features of diabetic vascular damage may play an important part. And it’s worth noticing that dyslipidemia also could accelerate the impairment of oocyte quality, as it promotes endothelial dysfunction and platelet hyperactivation, potentially causing vascular damage and imposing cytolipotoxic effects (9, 45). 4) Diabetes is known to be associated with an accelerated rate of the accumulation of advanced glycation end products (AGEs) (55). The accumulation of AGEs has been reported to be closely related to declining ovarian function (56). The glycation process causes protein damage, and the interaction of AGEs and their receptors could lead to the activation of a number of proinflammatory pathways, increased production of ROS in oocytes, and endothelial dysfunction via inactivation of endothelial nitric oxide synthase and prostacyclin synthase, thereby inducing a premature decline in ovarian function (48, 56). Moreover, AGEs were reported to accelerate the progression of nuclear maturation, though the mechanisms still unknown (57).

We also found that LDL-C and TC levels were positively correlated with LH and FSH, and negatively correlated E2 with LDL-C and TC levels in patients with T2DM aged between 51 and 60, suggesting perimenopausal changes of gonadotropins and E2 are correlated with dyslipidemia. According to previous studies, consistent cross-sectional and longitudinal associations of menopause with worsening lipid profile have been observed (58), and for decades the associations have been mainly attributed to estrogen deficiency. Negative associations of E2 with TC and LDL-C has been demonstrated in ERα-deficient models, women with E2 deficiency and postmenopausal women on E2 treatment (59–65), results consistent with our study findings. These protective effects of E2 can be largely attributed to its upregulation of low-density lipoprotein receptors (LDLR) on hepatic cells: 1) through nuclear receptor ER, E2 stimulates the expression of transcription factors related to cholesterol metabolism, which upregulates LDLR expression as a downstream target (66); 2) through G protein-coupled estrogen receptor, E2 prevents PCSK9-dependent LDLR degradation, thus reducing the levels of TC and LDL-C as well (67). In terms of gonadotropins, although studies regarding the role of LH in dyslipidemia are scarce, several previous studies addressing the links between FSH and lipid levels in postmenopausal women have demonstrated that higher FSH in postmenopausal women was related to higher levels of both TC and LDL-C, with stronger relations seen in younger compared to older postmenopausal women, which were close to the results of our results (29, 68). In the animal model of ovariectomized mice which simulated the postmenopausal period, an increase in both TC and LDL-C was also found when FSH was elevated independent of E2 (68); in postmenopausal women, adjusting the estrogen dose in HRT to attain a target FSH decrease might lead to beneficial alterations in TC and LDL-C (68). Further, studies on women in the menopausal transition suggests that an increase in FSH accompanying the menopause transition may contribute to the higher risk of CVDs including subclinical atherosclerosis after menopause (32–34). The biological mechanisms identified so far come down to the downregulation of LDLR expression (68). LDLRs in the liver determine the turnover rate of LDL-C and thus regulate the plasma LDL concentrations. FSH may interact with its receptors (FSHR) in hepatocytes and reduce LDLR levels, which subsequently attenuates the endocytosis of LDL-C, resulting in an elevated circulating LDL-C level (68). All in all, FSH might reduce the uptake and metabolism, especially degradation of LDL-C in liver (68).

According to our study, the LH and FSH levels began to increase obviously approximately from 45 years old, indicating the beginning of perimenopausal stage, which commonly lasts 2 to 10 years and is characterized by less regular menstruation (69); the relations between gonadotropins and LDL-C and TC were found in female patients with T2DM aged between 51 and 60, generally a perimenopausal or early postmenopausal state. Correspondingly, the indication from 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease directly recommends patients 40 to 75 years of age with LDL-C>70 mg/dL (1.8 mmol/L) to start moderate-intensity statin therapy for primary prevention once diagnosed with DM, indicating that the cholesterol management in women with T2DM should start from a relative early age to prevent from CVDs (70). Interestingly, randomized controlled trials suggest that hormone treatment achieves most cardiovascular benefits if initiated soon after menopause, and is potentially harmful if initiated late (>10 years) after menopause (26). However, the early prevention is not fully implemented clinical work, and diabetic women are less likely to be on optimal lipid-lowering therapy compared to men (71), though the British Heart Foundation states that the number of women living with CVDs is now roughly the same as the number of men (26). Combined with our finding of T2DM accelerating ovarian aging, more research is needed on metabolic changes in women with T2DM of an age range linked with drastic changes of sex hormone levels.

This study had some limitations. The retrospective study cannot infer cause and effect; the restricted sample size may not be generalized to the larger population; there is insufficient experimental evidence to explain the relationships we found. Further, the varied amount of subjects taking statins between age groups and groups divided by LH and FSH quartiles could cause bias in results; but the correlations we found in subjects aged between 51 and 60 were more likely to be underestimated since the percentage of statins taking was higher in groups of higher LH and FSH levels compared with groups with the bottom quartile of LH and FSH. Finally, this study emphasizes the necessity of an early management of ovarian aging in patients with T2DM, and lends credibility to the suggestion to adopt the cholesterol management as early as the age of 40 in women with T2DM; while the mechanisms of the association between T2DM and accelerated ovarian aging, and the correlations of gonadotropins with the lipid profile and other cardiovascular risks still require investigation.

Overall, the study indicates that patients with T2DM have accelerated ovarian aging, and the elevated LH and FSH levels together with the decreased E2 level caused by the accelerated ovarian aging are correlated with the occurrence of disturbed lipid profile in patients with T2DM. With an ever increasing number of female patients with T2DM diagnosed at younger ages, the accelerated ovarian aging and its adverse impacts in T2DM need to be carefully managed. Besides, further evaluation of these relations and the mechanisms underlying them is warranted, especially via prospective studies that can provide a clearer understanding for accelerated ovarian aging in patients with T2DM.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by medical ethics committee of the Affiliated Hospital of Qingdao University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YHW: designing and registering the work; the acquisition, analysis or interpretation of data for the work; drafting the work. YGW: agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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