Combined Intranasal Insulin, Saxagliptin and Metformin may reverse combined oral contraceptive induced Metabolic Syndrome: Study
Premenopausal women are active users of hormonal contraceptives. Commercially available formulations consisting of a synthetic estrogen and progestin constitute the globally recognized combined oral contraceptives (COCs). In addition to its contraceptive effects, constant administration of COC is also being explored as a therapeutic intervention against polycystic ovary syndrome (PCOS) and dysmenorrhea. However, the use of COC has been linked with disruption in body weight regulation, arterial blood pressure, glucose metabolism, and general homeostatic regulations in females. Endocrinologists and researchers in the field of reproductive health suggest that continuous prescription of COC should be revised with respect to these adverse effects.
Ethinyl estradiol (EE), synthesized from 17β-estradiol (E2), is the most used synthetic estrogen in COC; it is an estrogen receptor agonist. Levonorgestrel (LEV) is a use-alone emergency contraceptive pill and is also formulated with estrogen in some COC.
The combination of these hormones has been studied for their therapeutic efficacy in women who have PCOS, a pathological condition characterized by dysregulation in and carbohydrate metabolism in women. Generally, COCs from its inception have been linked with dysregulation of glucose homeostasis. The COCs containing norethindrone and EE have reportedly increased glycemia levels in premenopausal women; this effect was in tandem with COC containing levonorgestrel and EE.
Glycemic regulation is under the control of the hormone, insulin. Insulin resistance (IR) is a metabolic disorder that features a decreased response to both exogenous and endogenous insulin in cells, specific adipose tissues, skeletal muscles, and the whole body. IR is one of the major indicators and pathological driver of metabolic syndrome, a disease condition caused by a myriad of metabolic mishaps which features IR, hyperinsulinemia, glucose intolerance, and dyslipidemia.
Metformin is an oral hypoglycemic agent belonging to the biguanide class of antidiabetic agents. It is often used as first-line treatment of diabetes. It improves hyperglycemia primarily through its suppression of hepatic glucose production, increases insulin sensitivity, enhances peripheral glucose uptake, upregulates oxidation of fatty acid, and downregulates glucose absorption from the gastrointestinal tract.
Saheed Olanrewaju Afolabi and team set out to investigate the effect of combined oral contraceptives (ethinyl estradiol and levonorgestrel) and minipill (norethindrone) on adult female albino rats; and the possible ameliorative effect of single/combined administration of saxagliptin, intranasal insulin and metformin on the metabolic syndrome status.
64 female Wistar rats received either distilled water, norethindrone (NOR), COC, intranasal insulin (INI), metformin (MET), saxagliptin (SAX), INI+MET, and INI+SAX. After 8 weeks of exposure to COC, the animals were sorted into the therapeutic groups. Several parameters were assayed for, such as body weight changes, fasting blood glucose (FBG) level, insulin levels, inflammatory cytokines, and glycated hemoglobin (Hb1Ac).
The levels of FBG, insulin, and Hb1Ac were increased consequent upon COC treatment. Treatment with INI+SAX and INI+MET reduced significantly the levels of FBG and Hb1Ac; in addition, the level of insulin was significantly increased in the INI+MET groups (p ≤ 0:05). Serum lipid profile analysis showed a statistical reduction in high-density lipoprotein (HDL) level; this reduction was also significantly reversed in the INI+ SAX group. Reduced catalase activity observed in the COC group was reversed in the INI+MET group (p ≤ 0:05). A nonsignificant increase in the level of TNF-α as a result of COC treatment was reversed by INI and INI+MET treatment. Liver GLUT4 and G-6-phosphate levels were significantly increased by COC treatment, and this effect was reversed by INI+SAX in both assays, respectively (p ≤ 0:01).
Findings from this study show that chronic combined oral contraceptive treatment predisposes female albino rats to metabolic syndrome which features hyperglycemia, dyslipidemia, hyperinsulinemia, etc., all of which were featured in this present study. The use combination therapies particularly involving saxagliptin and metformin corrected some of these metabolic abnormalities that have a direct link to glucose metabolism. Thus, the metabolic syndrome status of combined oral contraceptive users should be closely monitored, and therapeutic interventions should be employed to prevent development of type 2 DM and other cardiovascular pathologies. A clinical study should be engaged in order to establish the translational relevance of these findings in women of reproductive age.
Source: Saheed Olanrewaju Afolabi , Joy Folahan, Olalekan Agede, and Olufunke Olorundare; Hindawi International Journal of Reproductive Medicine Volume 2021, Article ID 9693171, 12 pages https://doi.org/10.1155/2021/9693171
