# Insulin Sensitivity and Total Daily Insulin Dose Across Menstrual Cycle Phases in Premenopausal Women with Type 1 Diabetes Using Continuous Glucose Monitoring: A Comprehensive Literature Review

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### Background and Context

The intersection of female reproductive endocrinology and type 1 diabetes (T1D) management represents one of the most clinically consequential yet systematically underinvestigated domains in diabetology. Premenopausal women with T1D must contend not only with the inherent challenges of exogenous insulin replacement — a therapy that demands continuous titration against food intake, physical activity, stress, and illness — but also with the superimposed hormonal oscillations of the menstrual cycle, which exert measurable and clinically meaningful effects on insulin sensitivity, glycemic variability, and the risk of both hypoglycemia and hyperglycemia. Despite the fact that approximately half of all individuals with T1D are female, and that the reproductive years span several decades of disease management, the quantitative characterization of menstrual cycle–driven changes in insulin requirements has remained poorly defined in the published literature. This gap has direct consequences for clinical practice: without reliable, phase-specific estimates of insulin sensitivity changes, clinicians and patients are left to manage premenstrual hyperglycemia empirically, often through reactive rather than anticipatory dose adjustments.

The clinical importance of this question is underscored by the epidemiology of T1D in women. Women with T1D face a two- to three-fold greater risk of cardiovascular disease compared to their male counterparts with T1D, and a 40% higher rate of all-cause mortality, despite exhibiting more favorable cardiometabolic risk factor profiles at baseline (PMC10486136). Menstrual cycle irregularities — including oligomenorrhea, amenorrhea, and prolonged cycle duration — are more prevalent in women with T1D than in the general population, particularly in those with suboptimal glycemic control, and are themselves associated with increased cardiovascular risk (PMC9957258). The hormonal milieu of the menstrual cycle, particularly the progesterone-dominant luteal phase, has been mechanistically implicated in insulin resistance through multiple pathways, and observational data from CGM-equipped cohorts have begun to quantify the glycemic consequences of these fluctuations. Yet the literature remains heterogeneous, with studies varying widely in sample size, phase-verification methodology, insulin delivery modality, and the specific glycemic metrics employed, making definitive quantitative synthesis elusive.

Historically, the relationship between the menstrual cycle and glycemic control in T1D was recognized as early as the 1920s, when clinicians first noted that some women required insulin dose adjustments in the days preceding menstruation (PMC9962060). For most of the twentieth century, however, the absence of continuous glucose monitoring technology meant that these observations were based on intermittent capillary glucose measurements, which are poorly suited to capturing the dynamic, within-day glycemic patterns that characterize the luteal phase. The advent of flash glucose monitoring and real-time CGM systems has transformed the investigative landscape, enabling researchers to quantify time in range (TIR), time above range (TAR), time below range (TBR), mean glucose, and glycemic variability metrics across precisely defined menstrual cycle phases. Simultaneously, the proliferation of insulin pump therapy and, more recently, automated insulin delivery (AID) systems has introduced new complexity: AID algorithms may partially attenuate menstrual cycle–driven glycemic excursions through automated basal rate adjustments, potentially obscuring the true magnitude of the underlying insulin sensitivity change. The present review synthesizes the available quantitative evidence on the direction, magnitude, and clinical significance of menstrual cycle–phase differences in insulin sensitivity and total daily insulin (TDI) dose in premenopausal women with T1D using CGM, with particular attention to the mid-luteal versus early follicular phase comparison specified in the clinical question.

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### Molecular and Mechanistic Pathways

#### Progesterone-Mediated Insulin Resistance in the Luteal Phase

The luteal phase of the menstrual cycle is defined by the emergence and subsequent regression of the corpus luteum, which secretes both progesterone and estradiol in quantities that substantially exceed follicular phase concentrations. The systematic review by Giannini et al. (PMC9962060) notes that the increase in progesterone in the luteal phase is thought to determine the increased risk of hyperglycemia, and that worsening of insulin sensitivity in the luteal phase compared to the follicular phase has been reported across multiple studies using different measurement methods, though the pathophysiological mechanism underlying these changes remains unclear. The mechanistic basis for progesterone-induced insulin resistance is multifactorial and incompletely understood, but several converging lines of evidence implicate inhibition of the phosphoinositide-3-kinase (PI3K) signaling pathway as a central mechanism. As noted in the narrative review by Moser et al. (PMC9957258), progesterone has been implicated in insulin resistance during pregnancy, with the effect thought to be mediated by inhibition of the PI3K pathway as well as suppression of PI3K-independent signaling pathways. This mechanism is analogous to, though distinct from, the insulin resistance induced by progesterone during pregnancy, where placental progesterone concentrations are orders of magnitude higher but the downstream signaling impairment follows similar molecular logic.

In animal models, female mice with knockout of progesterone receptors exhibit lower fasting blood glucose levels and higher concentrations of circulating insulin compared to wild-type mice with intact progesterone receptors, providing direct genetic evidence for progesterone's role in modulating insulin sensitivity (PMC9957258). Furthermore, administration of synthetic progestins for contraceptive purposes has been associated with an increased incidence of type 2 diabetes in epidemiological studies, and enhanced progression of diabetes in mice has been associated with higher levels of circulating progesterone (PMC9957258). Progesterone may also impair the ability of pancreatic islet beta cells to secrete insulin in response to glucose, thereby delaying glucose disposal and reducing glucose tolerance — a mechanism that, while less directly relevant to T1D (where endogenous insulin secretion is absent or negligible), may contribute to altered glucagon dynamics and hepatic glucose production in this population (PMC9957258).

The accentuation of the "dawn phenomenon" — the early-morning rise in blood glucose driven by counter-regulatory hormone secretion — has been specifically implicated as a progesterone-mediated effect in the luteal phase of women with T1D. Several studies in the systematic review by Giannini et al. reported that the glycemic worsening observed during the luteal phase preferentially affected fasting glucose levels, consistent with an amplification of the dawn phenomenon by progesterone, suggesting that basal insulin adjustment should be the primary therapeutic lever for managing luteal-phase hyperglycemia (PMC9962060). This would suggest that basal insulin adjustment, rather than bolus insulin modification, should be the primary therapeutic lever for managing luteal-phase hyperglycemia — a clinically important distinction that has not been consistently validated across studies.

#### Estrogen's Dual and Context-Dependent Role in Glucose Metabolism

Estradiol, the predominant circulating estrogen during the reproductive years, exerts complex and context-dependent effects on glucose metabolism that are not straightforwardly insulin-sensitizing or insulin-desensitizing. Estradiol upregulates both glucose uptake and insulin secretion, protects pancreatic beta cell functionality and prevents apoptosis, inhibits gluconeogenesis pathways, and activates the ERα-PI3K-Akt signaling pathway to reduce insulin resistance in healthy premenopausal women (PMC9957258, PMC9962060). Estradiol also favors lipid oxidation over carbohydrate oxidation when lipids are available at higher concentrations, a metabolic shift that may reduce reliance on glucose as a fuel substrate and thereby lower the glycemic burden during the late follicular phase (PMC9957258, PMC13074237).

However, in the context of T1D, the vascular and metabolic effects of estradiol appear to be paradoxically altered. In the observational study by Hutchinson et al. (PMC10486136), 32 premenopausal women with T1D and 25 healthy controls completed experimental visits during menses (low estradiol) and the late follicular phase (high estradiol). Healthy controls exhibited a significant improvement in brachial artery flow-mediated dilation (FMD) from menses to the late follicular phase, while women with T1D exhibited the opposite response — a decrease in FMD during the late follicular phase (group-by-phase interaction p = 0.042; Cohen's d = 3.56 for the between-group difference at the late follicular phase, p = 0.024). Plasma TBARS (a marker of lipid peroxidation and oxidative stress) were significantly elevated in T1D women at both menses (p = 0.002; Cohen's d = 8.13) and the late follicular phase (p < 0.001; Cohen's d = 11.05), with a numerically greater rise across the cycle in T1D (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM, p = 0.133). These data suggest that in the presence of chronic hyperglycemia and oxidative stress, estradiol may paradoxically amplify vascular dysfunction rather than attenuate it — a finding with implications for understanding why the cardioprotective benefit of female sex is lost in T1D.

The mechanistic implication for insulin sensitivity is that the late follicular phase, characterized by peak estradiol concentrations, may not uniformly improve insulin sensitivity in women with T1D in the way it does in healthy women. The interplay between estradiol-mediated insulin sensitization and estradiol-mediated oxidative stress in the T1D milieu may produce a net effect that differs from either hormone in isolation. This complexity is further compounded by the fact that estradiol concentrations during the mid-luteal phase remain elevated (though below the pre-ovulatory peak), meaning that the luteal phase is characterized by the simultaneous presence of high progesterone (insulin-desensitizing) and moderately elevated estradiol (potentially insulin-sensitizing in healthy women, but oxidative-stress-amplifying in T1D). The net insulin sensitivity during the mid-luteal phase therefore reflects the algebraic sum of these opposing hormonal influences, which may explain the high degree of inter-individual variability observed in clinical studies.

#### Substrate Metabolism Shifts Across Menstrual Cycle Phases

Beyond direct effects on insulin receptor signaling, the menstrual cycle exerts measurable effects on substrate oxidation that have downstream consequences for glycemic management in T1D. During the follicular phase, when estradiol concentrations are rising and progesterone is low, there is a relative preference for carbohydrate oxidation during exercise, with higher rates of glucose utilization and lower rates of lipid oxidation at submaximal exercise intensities. During the luteal phase, the combination of elevated progesterone and sustained estradiol shifts substrate oxidation toward lipid utilization, reducing carbohydrate oxidation rates during low-to-moderate intensity exercise (PMC9957258).

The pilot study by Aparecido et al. (PMC9964010), which enrolled 11 eumenorrheic women of reproductive age (follicular group n=6, luteal group n=5) and assessed substrate oxidation by indirect calorimetry during 45-minute submaximal running exercise, reported significant between-group differences in relative energy derived from substrate oxidation. Specifically, the follicular group demonstrated substantially greater carbohydrate oxidation and lower lipid oxidation compared to the luteal group, with the luteal group relying more heavily on lipid as a fuel source. The authors attributed this pattern to the higher estrogen concentrations in the follicular phase, which they proposed favor changes in metabolism and performance during submaximal exercise. After eight HIT sessions, relative energy from CHOox increased by 18.89% in the follicular group and 25.50% in the luteal group, while relative energy from LIPox decreased by 8.45% and 3.46% in follicular and luteal groups, respectively (PMC9964010). While this study was conducted in women without diabetes and is explicitly classified as a pilot study with a very small sample size, the directional findings are consistent with the broader literature on menstrual cycle–phase effects on substrate metabolism. For women with T1D, a luteal-phase shift toward lipid oxidation during exercise would theoretically reduce the risk of exercise-induced hypoglycemia — a prediction that has been partially supported by some, but not all, exercise studies in T1D populations (PMC9957258).

The UK Biobank study by MacGregor et al. (PMC10709933), which analyzed data from 8,694 regularly menstruating pre-menopausal women, found significant non-linear associations between menstrual cycle phase and lipid profiles (total cholesterol, HDL cholesterol, LDL cholesterol, and total-to-HDL cholesterol ratio), but did not find statistically significant associations between menstrual cycle phase and glucose (EDF 1.3, p = 0.072), triglyceride (EDF 4.0, p = 0.066), or the triglyceride-glucose (TyG) index (EDF 3.6, p = 0.100) in the overall cohort. However, sub-group analyses revealed that variations in glucose and TyG index across the menstrual cycle were up to 25% greater in women with above-median fat mass and low physical activity, suggesting that metabolic risk factors amplify the magnitude of menstrual cycle–driven glycemic variability. This finding is particularly relevant to T1D, where the absence of endogenous insulin secretion means that even modest changes in insulin sensitivity translate directly into glycemic excursions that require active management.

#### The Role of Counter-Regulatory Hormones and the Hypothalamic-Pituitary-Ovarian Axis

The hypothalamic-pituitary-ovarian (HPO) axis is itself disrupted in a substantial proportion of women with T1D, with menstrual irregularities — including oligomenorrhea, prolonged cycle duration, and amenorrhea — occurring more frequently than in the general population (PMC9957258). These irregularities are associated with higher HbA1c levels: for each one-point increase in HbA1c, the duration of the menstrual cycle increased by approximately 5 days in women with T1D (Gaete et al., cited in PMC9957258). Schroeder et al. found that menstrual irregularities increased significantly when HbA1c levels exceeded 10% in an adolescent T1D population (PMC9957258). The disruption of the HPO axis in T1D is thought to reflect the combined effects of endogenous insulin deficiency (which reduces gonadotropin-releasing hormone pulsatility), exogenous hyperinsulinemia from intensive insulin therapy (which may facilitate ovarian androgen synthesis), and chronic hyperglycemia (which impairs ovarian function through oxidative stress and advanced glycation end-product accumulation) (PMC9957258).

The consequence of HPO axis disruption for the clinical question at hand is that a meaningful proportion of women with T1D may not exhibit the regular, predictable hormonal fluctuations that underlie the menstrual cycle–phase effects on insulin sensitivity described in the literature. Women with irregular cycles, anovulatory cycles, or luteal phase defects may experience attenuated or absent progesterone surges, reducing the magnitude of luteal-phase insulin resistance. Conversely, the narrative review by Moser et al. (PMC9957258) notes that women with T1D have a higher frequency of hyperandrogenism and polycystic ovarian syndrome than those without diabetes, with exogenous hyperinsulinemia from intensive therapeutic protocols potentially facilitating androgen synthesis and increasing the risk of PCOS in this population. Women with T1D who also have PCOS may therefore experience chronic, rather than cyclic, insulin resistance driven by hyperandrogenism and hyperinsulinemia, potentially confounding phase-specific analyses. These considerations underscore the importance of hormonal verification of menstrual cycle phase in research studies, a methodological standard that has been inconsistently applied across the existing literature.

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### Dose-Response and Pharmacokinetics

#### Magnitude of Insulin Sensitivity Change: Quantitative Estimates from the Literature

The central quantitative question — what is the mean difference in insulin sensitivity and total daily insulin dose between the mid-luteal and early follicular phases in premenopausal women with T1D using CGM — cannot be answered with a single, definitive pooled estimate from the available literature, because no meta-analysis has successfully pooled these data. The systematic review by Giannini et al. (PMC9962060), which is the most rigorous synthesis of this literature to date, explicitly states that "the retrieved data did not allow us to perform a meta-analysis to achieve quantitative results," citing the heterogeneity of methods and outcomes across the 14 included studies as the primary barrier. Nevertheless, the directional and approximate quantitative findings from individual studies provide a clinically useful, if imprecise, characterization of the magnitude of the effect.

Across the 14 studies included in the Giannini et al. systematic review (PMC9962060), published between 1990 and 2022, nine reported worsening glycemic control or higher risk of hyperglycemia in the luteal phase compared to the follicular phase. The glycemic metrics used to document this worsening included time above range (TAR), mean CGM glucose, the Kovatchev high blood glucose index (HBGI), and postprandial glycemic peaks. Four studies specifically assessed insulin sensitivity using direct or semi-direct methods (euglycemic clamp, Kalman filtering from closed-loop meal and insulin data, frequently sampled intravenous glucose tolerance test [FSIGT], and hyperglycemic hyperinsulinemic clamp), and all four reported worsening insulin sensitivity in the luteal phase compared to the follicular phase, though not all reached statistical significance. Two studies found no statistically significant differences in glucose metrics across menstrual cycle phases, and two found no statistically significant differences in insulin sensitivity.

The systematic review by Giannini et al. (PMC9962060) reports that, across the included studies, nine showed worsening glycemic control or higher risk of hyperglycemia in the luteal phase versus the follicular phase, expressed in terms of TAR, mean CGM glucose, HBGI, postprandial glycemic peaks, and glycemic response to clamp procedures. A larger retrospective study of 26 women with T1D found that approximately 65.4% of participants experienced cyclic changes in glycemia, with blood glucose rising from the early follicular to the late luteal phase (PMC9957258). The systematic review by Giannini et al. (PMC9962060) further reports that, across the included studies, worsening glycemic control or higher risk of hyperglycemia in the luteal phase was the most consistently observed finding, with some studies identifying differences across sub-phases including early follicular, mid-late follicular, periovulation, early luteal, mid-luteal, and late luteal periods.

Regarding total daily insulin dose (TDD), the Giannini et al. systematic review (PMC9962060) reports that four studies evaluated TDD as a measure of insulin sensitivity, while seven studies used direct methods such as the euglycemic clamp, FSIGT, insulin-glucose infusion test, hyperglycemic hyperinsulinemic clamp, or Kalman filtering. The review does not report a pooled quantitative estimate of TDD change across phases due to heterogeneity of reporting formats (PMC9962060). The narrative review by Moser et al. (PMC9957258) notes that women with T1D tend to increase their insulin doses when they experience reduced insulin sensitivity or high blood glucose during the luteal phase, and that this adjustment could increase the risk of hypoglycemia both during and after exercise due to higher levels of insulin in circulation. This observation highlights the clinical importance of the TDD question: the magnitude of the required dose increase determines both the therapeutic benefit (reduced hyperglycemia) and the iatrogenic risk (increased hypoglycemia) of luteal-phase insulin adjustment.

#### Phase-Specific Insulin Sensitivity Estimates from Direct Measurement Studies

The most methodologically rigorous estimates of the magnitude of insulin sensitivity change across menstrual cycle phases in T1D come from studies using direct measurement techniques. Four studies in the Giannini et al. systematic review assessed insulin sensitivity using direct or semi-direct methods and reported worsening of insulin sensitivity in the luteal phase compared to the follicular phase (PMC9962060). These methods included the euglycemic clamp, the Kalman filtering method, the FSIGT, and the hyperglycemic hyperinsulinemic clamp. Of these, the euglycemic clamp and Kalman filtering studies reached statistical significance, while the FSIGT and hyperglycemic hyperinsulinemic clamp studies did not. The divergence between these findings may reflect genuine differences in the populations studied, the specific phases compared, and the sensitivity of the measurement techniques employed, as well as the well-documented limitation that euglycemic clamp conditions do not reflect the real-world hyperglycemic state of T1D patients, potentially underestimating the true magnitude of insulin resistance in this population (PMC9962060).

#### Automated Insulin Delivery and Attenuation of Phase-Specific Effects

A particularly important pharmacokinetic consideration for the contemporary clinical question is the potential for automated insulin delivery (AID) systems to attenuate or eliminate the measurable differences in glycemic outcomes across menstrual cycle phases. Levy et al. (2022, cited in PMC9957258) found that insulin delivery and glycemic metrics remained stable throughout different phases of the menstrual cycle in 16 women with T1D using an automated insulin delivery system (t:slim X2 insulin pump with Control-IQ Technology and CGM). The authors suggested that this unexpected finding may reflect the mitigation of meaningful differences in glycemic outcomes as a result of more strategic, automated insulin delivery, as opposed to reactive changes in insulin delivery in an open-loop setting. This finding has significant implications for the interpretation of the broader literature: studies conducted in the era of multiple daily injections (MDI) or open-loop continuous subcutaneous insulin infusion (CSII) may overestimate the magnitude of the clinical problem in the contemporary AID era, while simultaneously underscoring the importance of understanding the underlying physiology for the development of AID algorithms that can proactively account for menstrual cycle–phase changes in insulin sensitivity.

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### Clinical Evidence and Implications

#### Observational CGM Studies in T1D: Glycemic Metrics Across Menstrual Cycle Phases

The most directly relevant clinical evidence for the user's question comes from observational studies that have used CGM to characterize glycemic patterns across menstrual cycle phases in women with T1D. The systematic review by Giannini et al. (PMC9962060) identified 14 eligible studies published between 1990 and 2022, with sample sizes ranging from 4 to 124 patients and between 1 and 6.5 menstrual cycles observed per patient. Not all of these studies employed CGM as the primary measurement modality: more recent papers (since 2004) used CGM parameters such as mean glucose, TIR, TAR, TBR, and the coefficient of variation, while earlier studies relied on patient self-reported glucose values or capillary tests (PMC9962060). The heterogeneity of these studies — in terms of phase-verification methodology, glycemic metrics, insulin delivery modality, and the specific phases compared — precludes formal meta-analytic pooling, but the directional consistency of the findings across nine of the fourteen studies provides meaningful clinical signal.

The most consistently reported finding across CGM-based studies is an increase in TAR (time above range, defined as glucose >180 mg/dL or >10 mmol/L) during the luteal phase compared to the follicular phase. This finding was reported as statistically significant in three of the studies reviewed by Giannini et al. (PMC9962060) and as a non-significant trend in three additional studies. The magnitude of the TAR increase varied across studies but was clinically meaningful in those that reported absolute values. The HBGI (high blood glucose index) was found to be significantly higher in the luteal phase in one study, and postprandial glycemic peaks were found to be significantly higher in the luteal phase in another study, suggesting that the insulin-to-carbohydrate ratio may need to be adjusted for meal boluses during this phase (PMC9962060).

The retrospective study of 26 women with T1D (cited in PMC9957258) is notable for its finding that approximately 65.4% of participants experienced cyclic glycemic changes, with blood glucose rising from the early follicular to the late luteal phase. This figure — that roughly two-thirds of women with T1D experience clinically meaningful menstrual cycle–driven glycemic variability — is frequently cited in the clinical literature as a benchmark for the prevalence of the "menstrual cycle phenomenon" in this population. However, it is important to note that this estimate is derived from a single retrospective study with a small sample (n=26) and may not be generalizable to the broader T1D population, particularly given the high prevalence of menstrual irregularities in T1D that would exclude many women from exhibiting regular, predictable phase-specific glycemic patterns.

#### Exercise Studies in T1D: Phase-Specific Glycemic Response

Only two studies have specifically examined the effect of menstrual cycle phase on glycemic response to exercise in women with T1D, and their findings are discordant (PMC9957258). McGaugh et al. (2020) examined glycemic response to prolonged (2-hour) aerobic exercise at approximately 45% VO2 peak while fasting in seven eumenorrheic women with T1D during the luteal and early follicular phases, and found no significant differences in glucose levels, carbohydrate consumption, or carbohydrate oxidation between the two phases before and during exercise; however, post-exercise nocturnal hyperglycemia was more frequent during the luteal compared to the early follicular phase (PMC9957258).

In contrast, Momeni et al. (2022) found a higher frequency of post-exercise hyperglycemia during the early follicular phase compared to the late luteal phase in nine eumenorrheic women with T1D performing non-fasting moderate aerobic exercise at 50% VO2 peak, and more glucose supplementation was required during the late luteal phase to prevent hypoglycemia during and after exercise (PMC9957258). This finding — that the late luteal phase is associated with greater hypoglycemia risk during exercise, rather than greater hyperglycemia risk — appears to contradict the broader literature suggesting that the luteal phase is characterized by insulin resistance and hyperglycemia. The authors attributed this observation to the higher levels of insulin in circulation during the late luteal phase as a result of dose increases made to counteract the reduced insulin sensitivity and higher glucose levels characteristic of this phase, which then predispose to hypoglycemia during exercise. This interpretation highlights the clinical complexity of managing insulin doses across menstrual cycle phases: the appropriate response to luteal-phase insulin resistance (increasing the insulin dose) may inadvertently increase hypoglycemia risk during exercise if the dose increase is not carefully timed and calibrated.

#### Longitudinal Observational Data: Insulin Requirements and Glycemic Control

The longitudinal observational study by Strotmeyer et al. (2003, cited in PMC9957258) found that women with T1D had more menstrual problems — including long cycles and long menstruation — before the age of 30 than their sisters and unrelated control participants without diabetes, but that these differences were no longer evident after the age of 30. This age-related attenuation of menstrual irregularities in T1D has implications for the generalizability of phase-specific insulin sensitivity findings: studies conducted predominantly in younger women with T1D may not reflect the experience of women in their 30s and 40s, who may have more regular cycles and therefore more predictable phase-specific glycemic patterns.

The cross-sectional study by Kim et al. (PMC9032389), analyzing data from 9,043 Korean women in the KNHANES V database, found that postmenopausal women had a 51% higher risk of diabetes compared to premenopausal women (adjusted OR = 1.51, 95% CI = 1.01–2.27, p = 0.047), and that women with menstrual irregularities had a 51% higher risk of diabetes overall (adjusted OR = 1.51, 95% CI = 1.10–2.07, p = 0.011). While this study did not specifically examine T1D or phase-specific insulin sensitivity, it provides population-level evidence that menstrual cycle regularity is associated with metabolic health outcomes, and that the hormonal environment of the premenopausal period is protective against diabetes-related metabolic deterioration. In the Kim et al. study, menstrual irregularities were significantly associated with diabetes risk in postmenopausal women (adjusted OR = 1.62, 95% CI = 1.12–2.42, p = 0.012) but not in premenopausal women (adjusted OR = 1.22, 95% CI = 0.64–2.32, p = 0.555), suggesting that the long-term metabolic consequences of menstrual irregularity may be mediated through mechanisms that become apparent only after the loss of ovarian hormone production.

#### UK Biobank Data: Menstrual Cycle Phase and Metabolic Markers in Pre-Menopausal Women

The UK Biobank study by MacGregor et al. (PMC10709933) provides the largest population-based dataset on menstrual cycle–phase associations with metabolic markers, analyzing data from 8,694 regularly menstruating pre-menopausal women (mean age 44.9 ± 2.8 years, mean BMI 26.2 ± 5.2 kg/m²). Menstrual cycle phase was estimated from self-reported days since last menstrual period and usual cycle length, standardized to a 0–1 scale (follicular phase 0.00–0.54; luteal phase 0.54–1.00). The study found significant non-linear associations between menstrual cycle phase and total cholesterol (EDF 3.4, p < 0.001), HDL cholesterol (EDF 2.9, p < 0.001), LDL cholesterol (EDF 3.6, p = 0.012), and total-to-HDL cholesterol ratio (EDF 5.4, p < 0.001), with total, LDL, and total-to-HDL cholesterol highest in the early follicular phase and declining during the luteal phase, and HDL peaking in the late follicular phase. Variation across the cycle ranged from 2.15% (LDL) to 4.17% (total-to-HDL ratio).

Critically for the present review, the UK Biobank study did not find statistically significant associations between menstrual cycle phase and glucose (EDF 1.3, p = 0.072), triglyceride (EDF 4.0, p = 0.066), or TyG index (EDF 3.6, p = 0.100) in the overall cohort (PMC10709933). However, sub-group analyses revealed that the associations between menstrual cycle phase and glucose, triglyceride, and TyG index were predominantly significant in women with above-median fat mass and fat-free mass, and in those with low or medium physical activity or below-median cardiorespiratory fitness, with variations in glucose and TyG index up to 25% greater in high-fat-mass, low-physical-activity subgroups. This finding suggests that the magnitude of menstrual cycle–driven glycemic variability is moderated by metabolic risk factors, and that women with T1D — who may have higher adiposity, lower physical activity, and greater baseline metabolic vulnerability than the healthy women in the UK Biobank cohort — may experience more pronounced phase-specific glycemic changes than would be predicted from population-level data in healthy women.

#### Substrate Oxidation Studies: Implications for Insulin Requirements

The pilot study by Aparecido et al. (PMC9964010), while conducted in women without diabetes, provides mechanistic context for understanding why insulin requirements might differ across menstrual cycle phases. The study enrolled 11 eumenorrheic women of reproductive age (follicular group n=6, luteal group n=5) and assessed substrate oxidation by indirect calorimetry during 45-minute submaximal running exercise. The authors reported significant between-group differences in relative energy derived from substrate oxidation, with the follicular group demonstrating substantially greater carbohydrate oxidation and lower lipid oxidation compared to the luteal group. The authors attributed this pattern to the higher estrogen concentrations in the follicular phase, which they proposed favor changes in metabolism and performance during submaximal exercise (PMC9964010). After eight HIT sessions, relative energy from CHOox increased by 18.89% in the follicular group and 25.50% in the luteal group, while relative energy from LIPox decreased by 8.45% and 3.46% in follicular and luteal groups, respectively (PMC9964010). These findings suggest that the luteal phase is characterized by a metabolic state that relies more heavily on lipid oxidation and less on carbohydrate oxidation during exercise, which would theoretically reduce the glucose-lowering effect of exercise and potentially reduce the risk of exercise-induced hypoglycemia in women with T1D during this phase — consistent with the observation by Momeni et al. that more glucose supplementation was required during the late luteal phase to prevent hypoglycemia during exercise (PMC9957258).

The narrative review by Moser et al. (PMC9957258) synthesizes the broader literature on substrate metabolism across menstrual cycle phases in eumenorrheic women without diabetes, noting that studies have found lower rates of glucose appearance and disappearance, less carbohydrate oxidation, lower total glycogen utilization, and higher fat oxidation in the luteal compared to the follicular phase in response to moderate-intensity endurance exercise. However, these findings are not universal: some studies found no significant differences in glucose utilization or substrate oxidation between phases, and the discrepancies may be attributable to differences in exercise intensity, duration, nutritional status, and individual variability in hormonal fluctuation. At higher exercise intensities (≥70% VO2 max), menstrual cycle phase effects on substrate oxidation appear to diminish, suggesting that the phase-specific metabolic differences are most pronounced at low-to-moderate exercise intensities (PMC9957258).

#### The Narrative Review by Moser et al.: Synthesis of T1D-Specific Evidence

The narrative review by Moser et al. (PMC9957258) is the most comprehensive synthesis of the available evidence on the menstrual cycle, exercise, and T1D, and provides the most directly relevant clinical context for the user's question. The review synthesizes evidence from observational studies, exercise intervention studies, and mechanistic research, and concludes that cyclic changes in blood glucose levels and insulin sensitivity have been reported in a subset of women with T1D throughout the menstrual cycle, with the most consistent finding being an increase in blood glucose and a decrease in insulin sensitivity during the luteal phase compared to the follicular phase. The review notes that approximately 65.4% of women with T1D (n=26) experienced cyclic glycemic changes with rising blood glucose from the early follicular to the late luteal phase in one retrospective study.

The review also highlights the cardiovascular implications of menstrual cycle irregularities in T1D, citing data showing a 20% higher risk of heart disease in women with irregular menstrual cycles over a 20-year follow-up period (n=13,714; PMC9957258), a 50% greater risk of non-fatal myocardial infarction or fatal coronary heart disease in women with very irregular versus very regular cycles (n=82,439; PMC9957258), and a hazard ratio of 1.42 for coronary heart disease mortality in women with irregular cycles (PMC9957258). These cardiovascular risk data underscore the importance of optimizing glycemic control across all phases of the menstrual cycle in women with T1D, not only for immediate glycemic outcomes but also for long-term cardiovascular health.

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### Safety Profile and Adverse Events

#### Hypoglycemia Risk During Luteal-Phase Insulin Dose Adjustment

The primary safety concern associated with menstrual cycle–phase insulin dose adjustment in women with T1D is hypoglycemia. The luteal phase is characterized by reduced insulin sensitivity and a tendency toward hyperglycemia, which prompts many women and their clinicians to increase insulin doses during this period. However, the magnitude of the required dose increase is difficult to predict at the individual level, and over-correction carries the risk of hypoglycemia — particularly during and after exercise, when the glucose-lowering effect of physical activity is superimposed on the increased insulin dose (PMC9957258). The study by Momeni et al. (cited in PMC9957258) found that more glucose supplementation was required during the late luteal phase to prevent hypoglycemia during and after exercise in nine women with T1D, suggesting that the combination of increased insulin doses and exercise-induced glucose lowering creates a particularly high-risk scenario for hypoglycemia during this phase.

The fear of hypoglycemia is itself a significant barrier to exercise participation in women with T1D, and the menstrual cycle adds an additional layer of complexity to this already challenging management problem. Females with T1D tend to consume less carbohydrates than T1D males to prevent activity-related hypoglycemia, and the fear of hypoglycemia may partly explain why females with T1D are less active than their male counterparts (PMC9957258). The occurrence and fear of hypoglycemia is a significant barrier to exercise for those with T1D, especially for females with T1D, and the menstrual cycle–driven changes in insulin sensitivity and glucose dynamics during exercise may amplify this barrier during specific phases of the cycle (PMC9957258). Clinicians advising women with T1D on exercise management should be aware that the appropriate insulin adjustment strategy may differ between the follicular and luteal phases, and that a dose increase appropriate for the luteal phase at rest may predispose to hypoglycemia during exercise.

#### Cardiovascular Risk Associated with Menstrual Cycle Irregularities in T1D

Women with T1D who experience menstrual cycle irregularities face an elevated cardiovascular risk that is independent of, and additive to, the cardiovascular risk associated with T1D itself. The vascular study by Hutchinson et al. (PMC10486136) demonstrated that premenopausal women with T1D experience a transient increase in cardiovascular risk during the late follicular phase of the menstrual cycle, driven by estradiol-mediated oxidative stress and endothelial dysfunction. The Hutchinson et al. study estimated that the observed reduction in FMD during the late follicular phase in T1D women corresponds to a transient increase in CVD risk of approximately 18% compared to healthy controls during this phase, based on the established relationship that every 1% reduction in FMD coincides with a 9% increase in future CVD risk (PMC10486136). While this estimate is derived from a relatively small study (n=32 T1D, n=25 controls) and should be interpreted with caution, it highlights the importance of considering vascular health — not only glycemic control — as an outcome of interest in studies of menstrual cycle–phase effects in T1D.

In a proof-of-concept subgroup analysis in the Hutchinson et al. study, FMD was overall higher in women with T1D using hormonal birth control (HBC+, n=9) compared to those not using HBC (HBC−, n=9) (p = 0.016; Cohen's d = 0.683), and TBARS increased more than two-fold in HBC− compared to HBC+ women (p = 0.030; Cohen's d = 0.563) (PMC10486136). These findings suggest that suppression of endogenous estradiol through HBC may attenuate the estradiol-mediated oxidative stress and endothelial dysfunction observed in T1D women during the late follicular phase, potentially offering a cardiovascular benefit in this population. However, the very small sample size of the subgroup analysis (n=9 per arm), the non-randomized design, and the use of various generations of oral contraceptives limit the strength of this conclusion, and the authors explicitly call for future randomized clinical trials to confirm these findings.

#### Safety of Automated Insulin Delivery in the Context of Menstrual Cycle Variability

The finding by Levy et al. (cited in PMC9957258) that insulin delivery and glycemic metrics remained stable throughout different phases of the menstrual cycle in 16 women with T1D using an AID system (t:slim X2 with Control-IQ Technology) suggests that contemporary AID systems may be capable of automatically compensating for menstrual cycle–driven changes in insulin sensitivity without requiring manual dose adjustments. If confirmed in larger studies, this finding would have important safety implications: it would suggest that women with T1D using AID systems may be at lower risk of both luteal-phase hyperglycemia (because the AID system automatically increases insulin delivery in response to rising glucose) and post-adjustment hypoglycemia (because the AID system can also reduce insulin delivery in response to falling glucose). However, the small sample size of this study (n=16) and the use of a single AID system limit the generalizability of this finding to other AID platforms and to women with more pronounced menstrual cycle–driven glycemic variability.

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### Unresolved Controversies and Disagreements

#### The Prevalence and Universality of the "Menstrual Cycle Phenomenon" in T1D

One of the most fundamental unresolved controversies in this literature is the question of what proportion of women with T1D experience clinically meaningful menstrual cycle–driven changes in insulin sensitivity and glycemic control. The estimate of approximately 65.4% from the retrospective study of 26 women (cited in PMC9957258) is widely cited but is based on a single small study with a retrospective design and no hormonal verification of menstrual cycle phase. The systematic review by Giannini et al. (PMC9962060) explicitly identifies the prevalence of the "menstrual cycle phenomenon" among women with T1D as unclear, noting that "data from individual studies are not generalizable to a large population of T1DM patients." Two studies in the systematic review found no significant differences in glucose metrics across menstrual cycle phases (PMC9962060), and two found no statistically significant differences in insulin sensitivity, suggesting that the phenomenon is not universal. The high degree of inter-individual variability in the magnitude and even the direction of the phase-specific glycemic change — with some women experiencing greater hyperglycemia in the luteal phase and others experiencing no change or even greater hypoglycemia — is a consistent finding across studies and represents a major challenge for the development of generalizable clinical recommendations.

The discordance between the two exercise studies in T1D populations (McGaugh et al. and Momeni et al., both cited in PMC9957258) is particularly striking and has not been resolved. McGaugh et al. found no significant between-phase differences in glucose during prolonged fasting aerobic exercise but more post-exercise nocturnal hyperglycemia in the luteal phase, while Momeni et al. found higher post-exercise hyperglycemia in the early follicular phase and greater glucose supplementation needs in the late luteal phase. These contradictory findings may reflect differences in exercise protocol (fasting vs. non-fasting state, exercise duration, exercise intensity), the specific phases compared (luteal vs. early follicular in McGaugh et al.; early follicular vs. late luteal in Momeni et al.), and the small sample sizes (n=7 and n=9, respectively) that make both studies highly susceptible to type I and type II errors. The Giannini et al. systematic review (PMC9962060) notes that the phenotype of the glycemic worsening found in the luteal phase is unclear: some studies suggest it affects postprandial glucose (favoring adjustment of meal boluses and insulin-to-carbohydrate ratios), while others suggest it affects fasting glucose through accentuation of the dawn phenomenon (favoring adjustment of basal insulin rates).

#### The Role of Estradiol: Insulin-Sensitizing or Insulin-Desensitizing in T1D?

A second major unresolved controversy concerns the net effect of estradiol on insulin sensitivity in women with T1D. In healthy women, estradiol is broadly considered to be insulin-sensitizing, and the follicular phase — characterized by rising estradiol and low progesterone — is generally associated with better insulin sensitivity than the luteal phase (PMC9957258, PMC9962060). However, the vascular study by Hutchinson et al. (PMC10486136) demonstrated that rising estradiol during the late follicular phase is associated with worsening endothelial function in women with T1D, mediated by estradiol-induced oxidative stress. This finding raises the question of whether estradiol's effects on insulin sensitivity in T1D are similarly paradoxical — that is, whether the late follicular phase might be associated with worse, rather than better, insulin sensitivity in women with T1D compared to healthy women.

The systematic review by Giannini et al. (PMC9962060) notes that the effect of estrogen and progesterone on insulin sensitivity and glycemic parameters remains unresolved, and that "on the one hand, estradiol may contribute to the increased risk of hyperglycaemia, and its lowering increases the risk of hypoglycaemia." This statement, which appears to contradict the conventional view of estradiol as insulin-sensitizing, is based on a study (cited in PMC9962060) that found an association between estradiol levels and hyperglycemia risk in T1D women. The mechanistic basis for this paradoxical finding is not fully established, but may relate to estradiol's promotion of lipid oxidation over carbohydrate oxidation (which could reduce glucose utilization and contribute to hyperglycemia in the absence of adequate insulin), or to estradiol's effects on counter-regulatory hormone secretion (which could amplify the glycemic response to hypoglycemia). The narrative review by Moser et al. (PMC9957258) acknowledges this complexity, noting that "the effect of oestrogen and progesterone on IS and glycaemic parameters remains unresolved and could, at least partially, explain blood glucose/IS fluctuations."

#### Automated Insulin Delivery: Does It Eliminate or Merely Attenuate Phase-Specific Glycemic Variability?

The finding by Levy et al. (cited in PMC9957258) that AID systems may eliminate measurable differences in glycemic outcomes across menstrual cycle phases is potentially transformative for clinical practice, but it is also potentially misleading. If AID systems compensate for luteal-phase insulin resistance by automatically increasing insulin delivery, the glycemic outcomes may appear stable while the underlying insulin requirements are substantially elevated. This distinction matters for several reasons: first, it means that the "true" magnitude of the insulin sensitivity change may be underestimated in studies conducted in AID users; second, it means that women transitioning from AID to open-loop therapy (e.g., during pregnancy or due to device failure) may experience more pronounced phase-specific glycemic variability than they have previously encountered; and third, it means that AID algorithms that do not explicitly account for menstrual cycle phase may be suboptimal during the luteal phase, potentially requiring higher insulin delivery rates that could increase hypoglycemia risk if the algorithm's predictive model does not anticipate the phase-specific change. The Giannini et al. systematic review (PMC9962060) explicitly calls for future studies to include data on insulin administration modality (AID, CSII, MDI) as a key covariate. The Moser et al. review (PMC9957258) further notes that as medical engineers move forward in developing closed-loop insulin delivery systems, new data on menstrual cycle–driven fluctuations in insulin sensitivity will help to better manage blood glucose during exercise in females with T1D — identifying AID algorithm development as a high-priority translational research goal.

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### Limitations of the Evidence Base

The limitations of the existing literature on menstrual cycle–phase effects on insulin sensitivity and total daily insulin dose in women with T1D using CGM are numerous, pervasive, and collectively prevent the generation of a definitive quantitative estimate of the mean difference between the mid-luteal and early follicular phases.

**Sample sizes across all identified studies are small.** The systematic review by Giannini et al. (PMC9962060) identified 14 eligible studies with sample sizes ranging from 4 to 124 patients and between 1 and 6.5 menstrual cycles observed per patient. The two exercise studies specifically conducted in T1D females had sample sizes of 7 and 9 participants, respectively (PMC9957258). These sample sizes are grossly insufficient to detect modest effect sizes with adequate statistical power, and the resulting estimates are highly susceptible to both type I and type II errors.

**Menstrual cycle phase verification is inconsistent across studies.** Eight of the 14 studies in the Giannini et al. systematic review (PMC9962060) defined menstrual cycle phases based solely on self-reported dates of menses, without hormonal confirmation of ovulation or luteal phase progesterone levels. This approach introduces substantial misclassification error, particularly in women with irregular cycles or luteal phase defects, and may dilute the estimated magnitude of phase-specific effects. Only five studies used blood or urine hormonal tests to identify ovulation and characterize the hormonal profile of each phase.

**Glycemic metrics are heterogeneous and not consistently aligned with current international guidelines.** The Giannini et al. systematic review (PMC9962060) notes that only four of the 14 included studies used the definition of hypo- and hyperglycemia according to the most recent international recommendations. Earlier studies used self-reported glucose values or capillary tests, from which mean glycemia and standard deviation were derived, making cross-study comparison difficult.

**Insulin sensitivity assessment methods are heterogeneous and may not reflect real-world T1D conditions.** The euglycemic clamp, which is the gold standard for insulin sensitivity measurement, maintains glucose at euglycemic levels that do not reflect the real-world hyperglycemic state of T1D patients, potentially underestimating the true magnitude of insulin resistance in this population (PMC9962060). The FSIGT and IGIT methods have their own limitations in the context of T1D, and the Kalman filtering method from closed-loop data is a relatively novel approach whose validity in this context has not been fully established.

**Confounding variables are inconsistently measured and controlled.** Physical activity, dietary intake, sleep quality, premenstrual syndrome symptoms, and stress — all of which can independently affect insulin sensitivity and glycemic control — are inconsistently measured or controlled across studies (PMC9962060). The Giannini et al. systematic review notes that only five of the 14 included studies collected data on lifestyle and diabetes care habits through wearable trackers, questionnaires, or validated scales.

**The literature is dominated by studies in eumenorrheic women, which may not represent the T1D population.** A substantial proportion of women with T1D experience menstrual irregularities, and the studies reviewed are predominantly conducted in women with regular cycles, limiting the generalizability of findings to the broader T1D female population (PMC9957258, PMC9962060).

**Publication bias may inflate the apparent prevalence and magnitude of the "menstrual cycle phenomenon."** Studies that find no significant phase-specific differences in glycemic outcomes or insulin sensitivity may be less likely to be published than those that find significant differences, potentially leading to an overestimate of the prevalence and magnitude of the effect in the published literature.

**The UK Biobank study (PMC10709933) was conducted in middle-aged women (mean age 44.9 years) without diabetes and relied on a single self-reported timepoint for menstrual cycle phase estimation rather than serial hormonal measurements; the cohort was 89.5% white, and the authors explicitly note that findings must be extrapolated to younger populations with caution, further limiting applicability to women with T1D.**

**The vascular study by Hutchinson et al. (PMC10486136) was conducted in relatively young, well-controlled T1D patients (mean HbA1c 8.6%) at a single academic center, and the proof-of-concept HBC subgroup analysis included only 9 participants per arm with non-randomly assigned HBC use, limiting generalizability.**

**The pilot study by Aparecido et al. (PMC9964010) had only 11 completers (follicular n=6, luteal n=5), was non-randomized, lacked a control group, and did not measure hormonal concentrations from blood samples.** The study was conducted in eumenorrheic women without diabetes, and the authors explicitly acknowledged the inability to measure sex hormones from blood samples as a limitation; findings therefore cannot be directly extrapolated to T1D populations.

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### Conclusions and Future Directions

#### What the Evidence Supports

The available evidence, synthesized across the systematic review by Giannini et al. (PMC9962060), the narrative review by Moser et al. (PMC9957258), and the supporting observational and mechanistic literature, supports the following conclusions regarding menstrual cycle–phase differences in insulin sensitivity and total daily insulin dose in premenopausal women with T1D using CGM:

First, a clinically meaningful "menstrual cycle phenomenon" — characterized by worsening glycemic control, increased time above range, and reduced insulin sensitivity during the luteal phase compared to the follicular phase — is present in a substantial subset of women with T1D, with the best available estimate suggesting that approximately 65.4% of women with T1D experience cyclic glycemic changes with rising blood glucose from the early follicular to the late luteal phase (PMC9957258). This estimate is based on a single retrospective study of 26 women and should be interpreted with caution, but the directional consistency of findings across nine of the fourteen studies in the Giannini et al. systematic review (PMC9962060) provides convergent support for the existence of the phenomenon.

Second, the mechanistic basis for luteal-phase insulin resistance is most plausibly attributed to progesterone-mediated inhibition of PI3K-dependent and PI3K-independent insulin signaling pathways, with potential contributions from progesterone-induced accentuation of the dawn phenomenon, altered substrate oxidation (reduced carbohydrate oxidation, increased lipid oxidation), and the complex interplay between estradiol and oxidative stress in the T1D milieu (PMC9957258, PMC9962060, PMC10486136).

Third, the magnitude of the insulin sensitivity change between the mid-luteal and early follicular phases cannot be precisely quantified from the available literature, because no meta-analysis has successfully pooled these data and the individual studies are too heterogeneous and underpowered to provide reliable point estimates. The Giannini et al. systematic review (PMC9962060) explicitly states that "the retrieved data did not allow us to perform a meta-analysis to achieve quantitative results." The directional finding — that insulin sensitivity is lower and insulin requirements are higher during the mid-luteal phase compared to the early follicular phase — is supported by the majority of studies, but the magnitude of the difference varies substantially across individuals and studies.

Fourth, the clinical implications of the menstrual cycle phenomenon extend beyond glycemic control to include cardiovascular risk: women with T1D experience a transient increase in endothelial dysfunction during the late follicular phase driven by estradiol-mediated oxidative stress (PMC10486136), and menstrual cycle irregularities in T1D are associated with a 20–50% higher risk of cardiovascular events in the general population (PMC9957258). These findings underscore the importance of optimizing glycemic control across all phases of the menstrual cycle in women with T1D.

#### What the Evidence Does NOT Support

The evidence does not support the generation of a specific, quantitative mean difference in insulin sensitivity or total daily insulin dose between the mid-luteal and early follicular phases that can be applied as a clinical recommendation for dose adjustment. The heterogeneity of the available data, the small sample sizes, the inconsistent phase-verification methodology, and the high degree of inter-individual variability collectively preclude the derivation of a reliable, generalizable estimate. The Giannini et al. systematic review (PMC9962060) explicitly concludes that "both questions raised by the present study remain partially unsolved, and published data do not allow us to achieve quantitative results."

The evidence also does not support the conclusion that the menstrual cycle phenomenon is universal in women with T1D: two studies in the Giannini et al. systematic review found no significant differences in glucose metrics across phases, and two found no statistically significant differences in insulin sensitivity (PMC9962060). The finding by Levy et al. (cited in PMC9957258) that AID systems may eliminate measurable phase-specific glycemic differences in 16 women with T1D suggests that the clinical relevance of the phenomenon may be attenuated in the contemporary AID era, though this finding requires confirmation in larger studies.

The evidence does not support a simple, uniform recommendation for luteal-phase insulin dose increases: the appropriate adjustment strategy (basal rate vs. bolus insulin vs. insulin-to-carbohydrate ratio) depends on the phenotype of the glycemic worsening (fasting vs. postprandial), which varies across individuals (PMC9962060). Furthermore, the risk of hypoglycemia during exercise in the late luteal phase — potentially exacerbated by dose increases made to counteract insulin resistance — means that any dose adjustment strategy must be carefully individualized and monitored (PMC9957258).

#### Future Research Directions

The following specific research priorities emerge from the gaps identified in the existing literature:

1. **Large, prospective, adequately powered studies with hormonal verification of menstrual cycle phase** are urgently needed to generate reliable quantitative estimates of the mean difference in insulin sensitivity and total daily insulin dose between the mid-luteal and early follicular phases in women with T1D using CGM. The Giannini et al. systematic review (PMC9962060) calls for future studies to adopt a prospective design with adequate sample size calculation, standardized glucose monitoring and insulin sensitivity estimation metrics, and systematic collection of data on sexual hormones, growth hormone, steroids, and androgens to confirm phase assignment.

2. **Standardized CGM-based glycemic metrics aligned with current international guidelines** (TIR 70–180 mg/dL, TAR >180 mg/dL, TBR <70 mg/dL) should be adopted as primary outcomes in all future studies, enabling cross-study comparison and eventual meta-analytic pooling (PMC9962060).

3. **Studies stratified by insulin delivery modality** (MDI, open-loop CSII, AID) are needed to determine whether AID systems truly eliminate phase-specific glycemic variability or merely compensate for it through increased insulin delivery, and to characterize the magnitude of the underlying insulin sensitivity change in AID users (PMC9957258, PMC9962060).

4. **Exercise studies in T1D women across menstrual cycle phases** are critically needed, given that only two such studies have been conducted to date, with contradictory findings and very small sample sizes (n=7 and n=9) (PMC9957258). Future studies should examine the effects of exercise type (aerobic vs. resistance vs. high-intensity interval), intensity, duration, and nutritional status on glycemic response across phases, and should include both fasting and non-fasting conditions.

5. **Development of AID algorithms that explicitly account for menstrual cycle phase** represents a high-priority translational research goal. Such algorithms could use CGM data patterns, self-reported menstrual cycle phase, or wearable biosensor data (e.g., basal body temperature, heart rate variability) to predict and proactively compensate for luteal-phase insulin resistance, potentially improving glycemic outcomes without increasing hypoglycemia risk (PMC9957258).

6. **Studies examining the cardiovascular implications of menstrual cycle–phase glycemic variability in T1D** are needed to determine whether the transient endothelial dysfunction observed during the late follicular phase (PMC10486136) is associated with long-term cardiovascular outcomes, and whether optimizing phase-specific glycemic control can attenuate this risk.

7. **Inclusion of women with menstrual irregularities and PCOS** in future studies is essential to characterize the full spectrum of menstrual cycle–related glycemic variability in the T1D population, rather than restricting analyses to eumenorrheic women (PMC9957258, PMC9962060).

8. **Systematic collection of lifestyle and hormonal covariates** — including physical activity, dietary intake, sleep quality, premenstrual syndrome symptoms, and levels of counter-regulatory hormones (cortisol, growth hormone, glucagon) — is needed to disentangle the independent contributions of progesterone, estradiol, and lifestyle factors to phase-specific glycemic variability (PMC9962060).

In summary, the available evidence establishes that a clinically meaningful menstrual cycle phenomenon — characterized by reduced insulin sensitivity and increased insulin requirements during the mid-luteal phase compared to the early follicular phase — exists in a substantial subset of premenopausal women with T1D, but the precise quantitative magnitude of this difference remains undefined due to the methodological limitations of the existing literature. Until adequately powered, prospective studies with standardized methodology are conducted, clinical management should be guided by individualized CGM data patterns across multiple menstrual cycles, with phase-specific insulin adjustments tailored to each patient's observed glycemic phenotype (PMC9962060). The development of AID algorithms that proactively account for menstrual cycle–driven changes in insulin sensitivity represents a promising avenue for improving glycemic outcomes in this population without increasing hypoglycemia risk (PMC9957258).

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