Type 2 Diabetes Delayed by Menopause Hormone Therapy

Mar 16, 2021 Editor: David L. Joffe, BSPharm, CDE, FACA
Author: Mit Suthar, PharmD. Candidate, LECOM School of Pharmacy 

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The mechanisms by which estrogens / hormone therapy improve glucose homeostasis and delay diabetes are not completely understood. 

Franck Mauvais-Jarvis, MD., director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, explained at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease: “During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension. They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”  

Almost 30 years ago, researchers investigated the connection between postmenopausal hormone use and the subsequent incidence of non-insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal US women aged 30-55 years. These women were registered in the Nurse’s Health Study and monitored for 12 years (Ann Epidemiol. 1992;2[5]:665-73).  

Interestingly, during this study they found that the patients who were on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. A newer study from 2009 analyzed the association between the use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women. These patients were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). This study also found that participants who were taking hormone therapy also experienced a 20% reduction in the incidence of type 2 diabetes.  

In another study called the Heart and Estrogen/Progestin Replacement Study researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes. 20 US centers reported on 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). The study participants received 0.625mg of conjugated estrogen with 2.5mg of medroxyprogesterone, or placebo, and were followed for 4 years. The research discovered that patients who were treated with hormone therapy had a 35% reduction in the incidence of diabetes.  

Dr. Mauvais-Jarvis stated that the strongest data came from the Women’s Health Initiative (WHI), which was a randomized, double-blind trial (Diabetologia. 2004; 47[7]:1175-87). This trial compared the effect of daily 0.625mg conjugated estrogen and 2.5mg medroxyprogesterone acetate with placebo during 5.6 years of monitoring.   
This trial also revealed a 20% decrease in the incidence of diabetes after 5 years. The researchers found that the protection from diabetes was present whether the WHI participants took just estrogen alone or estrogen plus medroxyprogesterone (N Engl J Med. 2016;374:803-6).  

Results from research published in 2006 from a meta-analysis of 107 trials (Diabetes Obes Metab. 2006;8[5]:538-54) found that in women without diabetes, hormone therapy decreased the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. Women with diabetes who took hormone therapy had their fasting glucose reduced by 11% and HOMA-IR by 36%.  

Dr. Mauvais-Jarvis explains that the mechanisms by which estrogens improve glucose homeostasis are not completely understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation. However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.” The idea that the benefits of hormone therapy are independent of weight loss for reducing the incidence of diabetes is certainly encouraging.  

Significant factors about the benefits and disadvantages of hormone therapy include the route of administration, and adverse effects of the therapies. Oral estrogens can increase liver exposure to estrogen, increase triglycerides, and increase clotting factors, but an advantage is that oral estrogen is a cheaper form than the transdermal form. Transdermal delivery of estrogen does not raise triglycerides, clotting factors, or inflammatory factors, and presents less exposure to the liver.  

Dr. Mauvis-Jarvis and colleagues also evaluated the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). The reason bazedoxifene was combined to estrogen was to preserve the beneficial effects of estrogen but block the estrogen in the breast and uterus, thus decreasing the risk of cancer.  

The unforeseen benefits of menopausal hormone therapy cannot be ignored in regard to the decreased incidence of diabetes in patients who take these hormonal therapies. While it is doubtful that hormone therapy will ever be approved for a diabetic indication due to the various complexities of said therapy, hormonal therapy should not be denied to patients with an approved indication who are at increased risk for developing diabetes.  

Practice Pearls: 

• Menopausal hormone therapy can significantly reduce the incidence of diabetes in patients who have an indication for hormone therapy and are at risk for developing diabetes. 
• Both older and more recent trials have demonstrated this reduction in incidence, which is around 20%  
• The mechanisms by which estrogens improve glucose homeostasis are not completely understood and the risks of estrogen therapy, such as cancer risk, must be accounted for on a patient by patient basis  

Brunk, Doug. “Menopause Hormone Therapy Found to Delay Type 2 Diabetes.” MDedge Endocrinology, MDedge, 31 Jan. 2020.  

Mit Suthar, PharmD. Candidate, LECOM School of Pharmacy