Emerging Perspectives on the Impact of Diabetes Mellitus and Anti-Diabetic Drugs on Premenstrual Syndrome. A Narrative Review

Although the impact of DM on PMS has been investigated in several studies, the results of those studies are not enough to understand their possible relation. Few studies have considered the possible association between DM and PMS [63‐65]. Some studies tackled the impact of the different menstrual cycle phases on blood glucose and IR [63, 64, 66‐72], while some studies investigated the impact of blood glucose changes on PMS symptoms, but in non-diabetic women [73, 74]. In terms of prevalence, Huang et al. [65] noted an association between DM and PMS. In contrast, Machfudhoh et al. [75] concluded that children with T1DM have no or only mild PMS. Similarly, Cawood et al. [63] also noticed that PMS symptoms in diabetic women are fewer than they are in non-diabetic women. Regarding severity, patients with diabetes with proper glycemic control did not appear to have milder PMS symptoms [63]. This finding defended the implication of DM in the development of PMS. Contrary, Creţu et al. [42] and Huang et al. [65] described diabetic women with insulin-related hyper-progesterone as being at higher risk for PMS. Regarding the impact of blood glucose level on PMS symptoms, Zarei et al. [74] concluded that hypoglycemia is a stimulating factor of PMS, which is in contrast to Cawood et al. [63] and [76], who reported some PMS symptoms (like anxiety and food craving) to be correlated to hyperglycemia and not to hypoglycemia.

On the other hand, as for the influence of the different menstrual cycle phases on blood glucose and insulin levels, Spellacy et al. [66] found no significant changes in plasma glucose or insulin levels in either the follicular or the luteal phases in both PMS and healthy-matched women. On the contrary, Trout et al. [72] reported high fasting glucose and low insulin sensitivity during the luteal phase, yet this finding was not significant. Dey et al. [64] similarly reported increased blood glucose level in the same phase. Also, Denicoff et al. [73] reported significant changes in glucose tolerance test in both luteal and follicular phases, but they denied PMS to be related to these changes.

These contradictory findings can be explained in the view of the methods used to evaluate the PMS–DM relationship. Although the diagnosis of PMS is an easy questionnaire-based process, the method and timing of blood glucose and insulin measurement made the interpretation of those studies challenging. Many studies relied on measuring fasting blood glucose and fasting insulin levels and estimating IR using the homeostatic model for assessment of IR (HOMA-IR). However, continuous blood glucose and insulin monitoring should have been ensured by using hyperinsulinemic-euglycemic clamp to avoid any subjective appraisal that might mislead the analysis of the blood glucose records. The exact timing between the change in blood glucose and the occurrence of mood alteration or the appearance of PMS physical symptoms has not been yet defined. In addition, the glycemic threshold for mood alteration has not been determined. Besides, individual variations and preexisting psychological and hormonal disorders could all affect the presentation of PMS in patients with diabetes.

To better understand the possible role of DM in PMS, it is important to notice that the important anabolic actions of insulin can help improve fatigue and the lack of concentration expressed by many patients. Insulin receptors additionally are widely distributed in the body, including the nervous system. In the brain, insulin receptors not only facilitate glucose delivery to this vital organ but they also improve synaptic plasticity and stimulate the release of neurotrophic factors (e.g., BDNF), hence exerting an anti-depressant action [77]. This finding was supported by many experimental studies and clinical trials in which insulin succeeded to improve depression symptoms through different mechanisms, including interacting with N-methyl-D-aspartic acid (NMDA) receptors in the hippocampus and by regulating neuronal cell growth and survival [78, 79]. Insulin also plays a vital role in the regulation of the autophagy process, as it facilitates the clearance of the damaged and aging organelles. Any defect of this cleansing process is associated with an increased ROS formation besides a subsequent neuronal cell death [80]. Insulin, in addition, has a major impact on brain serotonin by increasing the delivery of tryptophan to the brain, increasing the activity of the tryptophan hydroxylase enzyme, and decreasing the activity of the MAO enzymes, all of which enhance neuronal serotonin synthesis and concentration [81]. Thus, insulin deficiency and IR can be contributing factors for some PMS symptoms such as food craving, fatigue, lack of concentration, depression, and anxiety.

It seems that both hypoglycemia and hyperglycemia are linked to PMS, even though the fluctuation in blood glucose is not limited to the luteal phase. It is important to note that hypoglycemia is almost always represented as an acute episode because long-standing hypoglycemia can lead to irreversible brain damage. Through stimulating sympathetic nervous system and catecholamines secretion, hypoglycemia can be manifested with lack of concentration, anxiety, palpitation, nervousness, and irritability that mimic PMS symptoms [65, 72]. However, Denicoff et al. [73] concluded that despite the similarities between the symptoms of PMS and hypoglycemia, these two conditions can be effectively distinguished based on their respective spectrum of symptoms. On the other hand, hyperglycemia can be acute postprandial or chronic poorly controlled hyperglycemia. Acute hyperglycemia can cause a significant distortion of cognitive functions, e.g., information processing, attention, and working memory (letter/number sequencing) in addition to decreased alertness and happiness [42]. While chronic hyperglycemia may cause higher progesterone levels and neuropathy leading to PMS-related symptoms, this long-standing condition also allows for better cerebral adaptation.

Gut microbiota (GM) has recently gained researchers’ interest due to their major impact on body systems. GM play a pivotal role in the synthesis of many neurotransmitters (e.g., dopamine, serotonin, GABA, norepinephrine, and choline) and short-chain fatty acids (SCFA) (e.g., butyrate and succinate) that influence our body’s well-being. Gut dysbiosis (which refers to the systemic translocation of GM) has been speculated to mediate many psychological and somatic symptoms of PMS through inducing a state of systemic inflammation and neurodegeneration and causing abnormal hormonal levels [82]. Exposure of the systemic immune cells to the bacterial lipopolysaccharide (LPS) was found to increase the risk of T2DM [83] and was correlated to PMS as well [31]. Furthermore, marked differences in the GM composition were reported between diabetic and non-diabetic patients [84, 85].

The SCFAs synthesized by our GM have anti-inflammatory actions, being able to suppress IL-6, NO, and TNFα production and prevent the systemic translocation of the bacterial LPS [86]. SCFA was also found to be correlated with a lower risk of developing T1DM [87]. These SCFA also play a protective role in many neuropsychiatric disorders such as anxiety, depression, and neurodegeneration [88]. Bourassa et al. [89] mentioned in their study that the anti-oxidative action of butyrate can enhance the transcription of some protective proteins that are able to guard against neurodegeneration. In support of the possible GM role in PMS, Takeda et al. [90] described in their study a positive association between low levels of Butyricicoccus, Megasphaera, and Parabacteroides (known for their butyrate secretion action) and the prevalence of PMDs. The secretory function of GM, which includes serotonin, dopamine, and norepinephrine, shares at least in a part in the positive impact of probiotics on the aforementioned disorders. Moreover, Lactobacillus and Bifidobacterium were found to be able to metabolize glutamate to produce GABA [91] and can also improve the BDNF level [92].

Regarding female steroid hormones, GM can enhance estrogen concentration through secreting β-glucuronidase enzymes. These enzymes deconjugate the estrogen secreted in bile into active functioning forms. Sovijit and colleagues [93] also demonstrated a positive relation between Lactobacillus and progesterone levels.

Ever since their first introduction to the market, insulin and the insulin secretagogue sulfonylureas (SU) have been continuously developed to improve their pharmacokinetic and pharmacodynamic properties. Meglitinides have a similar action as that of SUs, but they act on different receptors with weaker binding affinity and faster dissociation [97, 98]. By preserving the anabolic and neuroprotective actions of insulin, insulin secretagogues are expected to improve some of the related PMS symptoms. Yet, increased insulin levels in the presence of insulin resistance may carry a higher risk of PMS through the hazardous actions of hyperinsulinemia, e.g., PCO [48].

SUs have the highest risk of hypoglycemia among the different anti-diabetic drugs. As mentioned before, hypoglycemia associated with catecholamine surge is manifested by PMS-like symptoms [65, 96]. Moreover, chlorpropamide, one of the old-generation SUs has the tendency to cause fluid retention due to an anti-diuretic hormone (ADH)-mediated action [99]. This action could aggravate the fluid retention and mastalgia experienced during PMS. It is to be noted also that chlorpropamide has been reported to increase serotonin levels by decreasing the latter’s metabolism [100]. Tolbutamide, another old-generation SU, has shown a positive impact on the activity of the serotonergic neurons [101]. Along with the cross-talk between SUs and serotonin, SU can also increase GABA activity through the inactivation of the ATP-sensitive K⁺ channels in the substantia nigra, improving the PMS-related anxiety symptoms and improving the pattern of sleep [102]. Both SUs and meglitinides possess anti-inflammatory actions that may contribute to improving PMS pathogenesis. Meglitinides were found to decrease oxidative stress and inflammatory markers such as IL-6, IL-18, and also TNFα. Similarly, the newer-generation SU glibenclamide was found to be able to inhibit the nuclear factor kappa B (NF-кB)-mediated inflammatory pathways and to decrease the secretion of some inflammatory cytokines (TNF-α, IL-1β, ROS). Through inhibiting the depolarization of the sulfonylurea type 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channels, glibenclamide can also protect against neuronal cell death [103, 104].

Metformin was the first known insulin-sensitizing agent pursued by the French physician Jean Sterne in 1957. The insulin-sensitizing action of metformin is executed by increasing peripheral glucose uptake and utilization that ensures euglycemic level. Other anti-diabetic actions of metformin include reducing hepatic gluconeogenesis, decreasing intestinal glucose absorption, and stimulating satiety [104, 105].

The new insights into the role of metformin in upstreaming the AMP-activated protein kinase (AMPK) have provided a unified explanation for the beneficial actions of metformin, not only as an anti-diabetic drug, but also in other metabolic, endocrinal, and neuropsychiatric disorders [104]. AMPK activation has been linked to many cellular processes, for example glucose and lipid metabolism, autophagy, and apoptosis, in addition to mediating an anti-oxidant effect. AMPK is also one of the downstream regulators of the tumor suppressors such as p53 [106].

Estradiol action on ERα was found to repress the AMPK activity and hence increase the risk for estrogen-dependent breast and endometrial cancers [107]. Metformin in turn has the potential to inhibit the expression of the aromatase enzyme, decreasing estrogen production. Metformin can also inhibit the nuclear translocation of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2), a coactivator of aromatase expression, and subsequently decreases estrogen concentration [108]. As far as its effect on sex hormones regulation, metformin has a unique place among all the anti-diabetic drugs in patients with PMS with abnormal high estrogen levels or estrogen sensitivity. Furthermore, in PCO patients with relatively low estrogen, metformin can treat hyperandrogenism, improve plasma estrogen levels, normalize menstrual irregularities, increase progesterone receptor expression, and improve progesterone concentration [109‐113]. These actions suggest a possible impact for metformin in PMS according to the baseline estrogen level. The anti-inflammatory actions of metformin could also aid in improving PMS symptoms. At the cellular level, the anti-inflammatory effects of metformin include reducing the expression of NF-кB, decreasing NF-кB-mediated inflammatory signals, and inhibiting the differentiation of monocyte into macrophages. It also reduces the production of TNF-α, IL-6, and IL-8 from epithelial cells and macrophages. These findings are supported by a meta-analysis that included 216 clinical trials carried out on PCO patients where metformin significantly reduced CRP levels [114]. The antioxidant role of metformin is carried out through several mechanisms: (1) direct trapping of hydroxyl radicals, (2) activation of antioxidant enzymes such as catalase, which is the main decomposer of H₂O₂, and (3) reducing the transcription and activation of NADPH oxidase 4 (NOX4), which is a major source of oxidative stress [115].

At the level of the nervous system, metformin has shown a favorable impact on anxiety and depression secondary to diabetes by influencing GABA and serotonin actions. Metformin exerts its action on the GABAergic system by directly regulating the number of neurotransmitters released and improving the expression of the receptors on the postsynaptic membrane [116]. Fan et al. [117] demonstrated that metformin potentiates inhibitory synaptic transmission by enhancing the postsynaptic accumulation of GABA_A receptors in the cell membrane by activating the AMPK- Forkhead transcriptional factor (FoxO3a) signaling pathway and increasing the expression of GABA_A receptor-associated protein. Moreover, the antidepressant effect of metformin observed in diabetic and PCO patients could be attributed to the elevation of serotonin and norepinephrine levels in the brain and the modulatory action of metformin on the hypothalamic serotonin axis [118, 119]. Metformin can also stimulate the release of serotonin from the enterochromaffin cells via neuronal and non-neuronal mechanisms. Yet, metformin may inhibit the uptake of serotonin from the intestinal lumen, leading to the accumulation of serotonin in the gut [120]. It remains uncertain whether this action would have a positive impact on the brain's serotonin levels.

Thiazolidinediones (TZDs), also called glitazones, elicit their insulin-sensitizing action either through a direct pathway (the fatty acid steal hypothesis) or indirectly (via modulating the adipokines release and upregulating the adiponectin production genes) by way of being selective agonists to the transcription factor, nuclear peroxisome proliferator-activated receptors (PPARs). Although PPARs exist in three isoforms, PPAR-α, PPAR-β, and PPAR-γ, TZDs possess a stronger binding affinity to PPAR-γ subtype [121].

Genetic studies have linked genetic polymorphism of PPAR-γ to PCO pathology, suggesting a link between PPAR-γ and the hypothalamic–pituitary–gonadal axis. Clinical studies in addition have reported an effect for TZDs therapy on improving hyperandrogenism and decreasing high LH levels in PCO patients [122]. Furthermore, adiponectin receptors (AdipoR1 and AdipoR2) were found to be regulated by PPAR-γ. These adiponectin receptors are widely expressed along the hypothalamic–pituitary–ovarian axis where they exert an inhibitory effect on the secretion of GnRH from hypothalamic cells. In the gonadotropic cells of the pituitary gland, adiponectins can stimulate LH and FSH synthesis and secretion. Finally, at the ovarian level, adiporeceptors expressed in the human granulosa cells regulate steroidogenesis, increasing progesterone and estradiol secretion in the presence of FSH and IGF-1 [123, 124]. In vitro studies illustrated the ability of TZDs to inhibit progesterone and estradiol secretion by human granulosa cells obtained from young women after hCG stimulation for in vitro fertilization, or from PCO patients. This can be attributed to the negative effects of TZDs on the activity of the steroidogenic enzymes: 3-beta-hydroxysteroid-dehydrogenase (3-βHSD) and the aromatase enzyme [125, 126]. Notably, Froment et al. [126] stated that treatment by TZDs does not seem to affect the secretion levels of prolactin, FSH, or LH.

The engagement of TDZs in regulating the above-mentioned hormones is hypothesized to impact PMS outcome, especially that TZDs may have a neuroprotective and an anti-inflammatory potential in the central nervous system. These actions are mediated by the TZDs’ inhibitory activity on the ability of macrophages to produce TNFα, IL-6, inducible nitric oxide synthase, COX-2, and IL-1β, through the down-regulation of their genes. This is along with the TZDs’ positive action on adiponectin genes, which are known to possess a potent anti-inflammatory action as well [127, 128]. Being able to ameliorate the chronic inflammatory status seen in insulin resistant, TZDs may help to attenuate the PMS inflammatory etiology.

TZDs, in some clinical studies, have demonstrated a positive potential in the treatment of major depression, especially when associated with insulin resistance. This finding was supported by a double-blinded randomized controlled trial (RCT) that assessed the effect of pioglitazone as an adjuvant treatment on depressive symptoms. The authors stated that there was a significant improvement in depression symptoms, but only in patients with insulin resistance, as a consequence of a better glucose homeostasis [129]. Another RCT by Sepanjnia et al. reported pioglitazone as a beneficial and safe short-term adjunctive modality in non-diabetic patients with depression as it showed higher rates of early improvement [130].

It was reported that TZDs are associated with dose-related fluid retention in about 20% of treated patients. In most patients, the edema is mild and responds to diuretics [131]. However, in diabetic women with PMS symptoms, TZDs may increase the burden of edema and breast tenderness. TZDs are not known to cause hypoglycemia when used as monotherapy. However, hypoglycemia may develop when being administered with other oral hypoglycemic drugs (particularly sulfonylurea), or when concomitantly prescribed with serotonin selective reuptake inhibitors (SSRIs) [132, 133]. The interaction with the later drug is particularly of great concern as SSRIs are commonly prescribed for PMS management. TZDs have other drug–drug interactions of special interest in patients with PMS, particularly the concomitant administration of pioglitazone with oral contraceptives containing ethinyl estradiol or norethindrone, which are prescribed in some cases either for birth control or to improve PMS symptoms. This combination may lead to a decrease in the plasma concentrations of the contraceptive hormones and consequently to the loss of their contraceptive effect [134].

In brief, the use of TZDs in patients with diabetes and PMS carries many concerns, despite the potent role of TZDs in improving insulin resistance and their anti-inflammatory potential that are expected to improve the diabetic-related PMS pathologies. Yet, TZDs increase the incidence of fluid retention, interact with sex hormones, and most importantly their concomitant use with SSRI carries higher risk for hypoglycemia.

Incretins are a group of gut peptides that stimulate insulin secretion and glucose homeostasis after nutrient intake. Glucagon-like peptide 1 (GLP-1) is one of those incretins. It is secreted from the intestinal epithelial L-cells to act on GLP-1 receptors (GLP-1Rs) which mediate its metabolic and extra-metabolic actions [135]. GLP-1 protects against hyperglycemia by enhancing insulin secretion through the regulation of the ATP-sensitive K⁺ channels in the pancreas. They can also inhibit glucagon secretion through the activation of the GLP‐1 receptors present in the pancreatic α-cells by a protein kinase A (PKA) -dependent inhibition of P/Q‐type Ca²⁺ channels in the pancreas. This action suppresses glucagon exocytosis [136, 137]. Based on these actions, GLP-1 R agonists (GLP-1RAs), e.g., liraglutide, exenatide, and semaglutide, are now approved as first-line agents for the management of T2DM [138].

GLP-1RAs have some neuro-endocrinal-metabolic actions that might link them to PMS. Although experimental studies have demonstrated that the acute activation of GLP-1R could increase serotonin turnover, chronic GLP-1RA administration has shown improvement in the serotonin receptor expression in the amygdala where it succeeded to implement an anti-depression action [139]. GLP-1RAs, in addition, stimulate the activity of the carbonic acid decarboxylase enzyme, increasing the decarboxylation of glutamate into GABA, and hence elevating brain GABA levels [140]. As regards the endocrinal effects, despite the shortage of information on the clinical effects of GLP-1/GLP-1RAs on the hypothalamic–pituitary–ovarian hormones, experimental studies have demonstrated a potent effect of GLP-1RAs on regulating the hypothalamic–pituitary–adrenal axis. GLP-1RAs can suppress aldosterone production, which may improve fluid retention in the premenstrual phase [141]. In rats, GLP-1RAs also exhibited a positive impact on estradiol and progesterone levels along the estrous cycle [142]. In humans, a close relation between progesterone and GLP-1 has been recognized, as enteral progesterone was found to increase plasma levels of GLP-1. In addition, progesterone receptor membrane component 1 (PGRMC1) expressed on pancreatic β cells was found to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1 [143].

GLP-1RAs exert an anti-inflammatory effect on vascular endothelial cells by upregulating the activity and the expression of the endothelial nitric oxide synthase (eNOS) and by inactivating the NF-кB signaling pathway [144]. Unlike other antidiabetic drugs, GLP-1RAs do not cause hypoglycemia, even in combination regimens. So these drugs are not expected to cause PMS-like symptoms that are related to hypoglycemia. GLP-1RAs can also suppress food intake by acting on different areas in the hypothalamus and the hindbrain, and by means of preserving free leptin levels. Induction of satiety would protect diabetic women from the hazards of food craving on their blood glucose level during the PMS phase [145]. The main adverse effects of GLP-1RAs are gastrointestinal upset (mainly nausea), headache, and nasopharyngitis. Yet these symptoms do not usually result in drug discontinuation [146].

In the body, GLP-1 is rapidly metabolized and inactivated by the dipeptidyl peptidase IV enzyme (DPP 4). Therefore, DPP4 inhibitors (e.g., sitagliptin, linagliptin, anagliptin, saxagliptin) are approved as T2DM therapies. By preventing the diabetic metabolic hazards, these drugs can ameliorate the DM-related PMS. This group of drugs can in addition suppress oxidative stress, fibrosis, and apoptosis, and they additionally showed a cardioprotective and renal protection power [147]. DPP4 substrates were found to mediate stress, anxiety, depression, and schizophrenia. Thus, the anti-inflammatory and pleiotropic actions of the DPP4 inhibitors could ameliorate the PMS pathophysiology as well [148, 149]. In support of these postulations, sitagliptin was suggested as an alternative to metformin in PCO patients who are intolerant to metformin [150]. These findings raise the hope that DPP4 inhibitors could attenuate some PMS etiologies and have a positive impact on mood disorders, which can help to minimize the mood swings reported in PMS.

Alpha-glucosidase enzymes are located in the brush border of the enterocytes and are greatly responsible for hydrolyzing non-absorbable oligosaccharides and polysaccharides into monosaccharides that can be easily absorbed. The alpha-glucosidase inhibitors (acarbose, miglitol, and voglibose) are pseudo-carbohydrates that can competitively and reversibly inhibit these intestinal enzymes to decrease the postprandial glucose load. Acarbose is poorly absorbed and is excreted unchanged in stool, with up to 30% undergoing metabolism primarily via fermentation by the colonic microbiota [151]. Similarly, voglibose is slowly and poorly absorbed and is rapidly excreted in stool [152]. In contrast, miglitol is completely absorbed from the gut and eliminated by the kidneys [153].

The alpha-glucosidase inhibitors by restoring the normal glucose tolerance can assist in reducing the diabetic-related complications, particularly those that can be considered PMS-related. Acarbose, in addition, appears to have some additive extra-antidiabetic effects when compared to miglitol and voglibose. Acarbose was found to be able to stabilize carotid plaques, improve lipid profile, and reduce inflammation. An RCT, conducted by Ciotta et al. [154] on 30 normally weighting PCOS patients, showed that eight patients who were treated by acarbose resumed their normal menstrual cycles with a significant decrease in the acne/seborrhea score. This clinical improvement was linked to significant declines in the insulin response to glucose load and an additional improvement in LH, total testosterone, and androstenedione levels. There was a significant increase in the serum concentrations of the sex hormone binding globulin as well. Notably, prolactin, 17-hydroxyprogesterone, dehydroepiandrosterone sulphate, and FSH serum concentrations did not show any significant changes. In the same context, Tuğrul et al. [155] stated that acarbose treatment significantly decreased basal insulin concentration, LH/FSH ratio, total testosterone, very low-density lipoprotein (VLDL), and triglyceride levels, with a significant enhancement in HDL level [156]. These effects can not only improve diabetic control and guard against diabetic complications but also may improve the hormonal profile in susceptible PMS-PCO patients.

By interfering with the degradation of complex carbohydrates into glucose, alpha-glucosidase inhibitors will eventually increase the amount of the undigested carbohydrates delivered to the colon. While these complex carbohydrates are then broken down by bacteria in the colon, causing some gastrointestinal side effects such as flatulence (78% of patients) and diarrhea (14% of patients), these complex carbohydrates in fact favor the growth of the beneficial gut microbiota instead of the harmful strains. This selective action will guard against gut dysbiosis and results in decreasing the systemic inflammatory cytokines levels in patients with diabetes and increasing the butyrate levels [157, 158].

Sodium-glucose cotransporter-2 (SGLT2) inhibitors work as anti-diabetic drugs through enhancing glucosuria. Dapagliflozin was the first SGLT2 inhibitor to be approved for the treatment of T2DM in Europe in 2012. Then followed the approval of canagliflozin, empagliflozin, and tofogliflozin [159]. SGLT2 inhibitors act on Na⁺-glucose cotransporters present in the apical membrane of the early proximal tubules of the kidney where the bulk of glucose uptake occurs [160]. They do not cause hypoglycemia unless combined with insulin secretagogues, especially sulfonylureas [161]. Although this hypoglycemia is not confined to the luteal phase, they may induce PMS-like symptoms.

SGLT2 inhibitors showed an anti-inflammatory potential through different mechanisms. They reduce hyperglycemia and sequentially inhibit glucotoxicity-mediated inflammation, such as endothelial dysfunction and oxidative stress. By facilitating glucosuria, SGLT2 reduces hyperuricemia and decreases the insulin/glucagon ratio, where the latter enhances ketonemia and the associated release of the pro-inflammatory cytokine. SGLT2 inhibitors support the activation of the eNOS, which mediate their cardiac and renovascular protective effects [162].

There is no evidence that SGLT2 inhibitors affect sex hormones, however there is a hypothesis that weight loss associated with SGLT2 inhibitors, particularly canagliflozin, may reduce aromatase activity, which may lower the production of estradiol due to the decreased fat tissue mass [163].

The diuretic effect of SGLT2 inhibitors made them the anti-diabetic drugs of choice for T2DM with heart failure. This action may show advantage in PMS women with fluid retention [164]. In addition, there is evidence that SGLT2 inhibitors have a sympatholytic activity. Although the mechanism of sympathetic inhibition with SGLT-2 inhibitors is not fully understood, it might be of a great benefit in patients with diabetes and PMS to alleviate the sympathetic derived anxiety disorder [165]. Obviously, improving diabetic control would also alleviate the speculated impact of DM on the PMS pathogenesis.