Case 2

A 53-year-old G3 P3 is referred by her internist for irregular, heavy menstrual bleeding and chronic anemia. The patient reports that her vaginal bleeding has occurred at 2- to 4-month intervals over the last year and these episodes have ranged from 2 to 12 days in duration. She says she has been told that she remains anemic despite iron therapy. The woman reports having hot flushes six to eight times per day over the last 6 months, with disruption of her sleep pattern, increased irritability, and a decreased short-term memory. Based on an abnormal glucose- tolerance test, she has been diagnosed as having adult-onset diabetes. Her medications include metformin (1500 mg/day), glipizide (10 mg/day), and hydrochlorothiazide/triamterene (50/75 mg qd).

On examination, the patient’s blood pressure is 136/86 mm Hg; pulse is 84 per minute; height is 5’3”; and weight is 226 lb. General examination is normal. On pelvic examination, the vulva and vagina are estrogenized, cervix is normal, uterus and adnexa are not palpable, and stool is guaiac negative. An endometrial biopsy is performed that shows disordered proliferative endometrium without hyperplasia.

Is this patient a candidate for estrogen replacement therapy?

Discussion
Non-insulin-dependent diabetes mellitus (NIDDM, Type II) affects 12 to 14 million Americans over the age of 20 years. This disorder represents a continuum, beginning with impaired glucose tolerance with progression to NIDDM. It is estimated that approximately 3% of patients per year will develop NIDDM. Individuals who may be at risk include patients with a previous history of gestational diabetes mellitus, a family history of NIDDM, and exogenous obesity with a body mass index > 27 kg/m².

In this patient who presents with perimenopausal symptoms of hypoestrogenism, and oligo-ovulation, ERT would ameliorate her hot flushes and mood changes, improve her sleep pattern, and provide a source of progestin to stabilize her endometrium. Recent studies in menopausal women indicate that use of ERT can improve insulin sensitivity and carbohydrate metabolism (Figure 2).¹ These studies suggest that fasting insulin levels remain unchanged while 2-hour postprandial insulin levels are actually lower during treatment with ERT.

Small, randomized trials of estrogen use in women with NIDDM suggest that glucose levels throughout the day are higher in those receiving placebo than in patients taking conjugated equine estrogens (Figure 3). Moreover, the postprandial increase in serum triglyceride levels is lower during estrogen therapy than when placebo is being taken (Figure 4).² For this patient, it is recommended that a baseline cholesterol profile with triglyceride levels be obtained prior to and 4 to 6 weeks after beginning ERT.

The improvement in glucose metabolism may be related to one of three factors: (1) estrogen’s impact on glucose transporter protein action; (2) estrogen’s ability to decrease peripheral insulin resistance; or (3) a reduction in hepatic glucose production. Taken together, these studies suggest that for this patient with NIDDM, ERT may be beneficial for relief of her hypestrogenic symptoms, reduce her risk for endometrial hyperplasia, and improve her overall carbohydrate tolerance.

Figure 2 Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial (1989-1991) Post Rx Impact of estrogen replacement therapy on glucose metabolism in menopausal women randomized to receiving either placebo, CEE, or combinations of CEE with progestin during a 3-year randomized clinical trial. Source: The Writing Group for the PEPI Trial.1

Figure 3 ERT and AODM Effect of estrogen replacement therapy on 25 menopausal women with NIDDM randomized to receive either placebo or CEE 0.625 mg/day for 8 weeks in a randomized, cross-over trial. Source: Friday KE, et al.2

Figure 4 ERT and AODM Effect of estrogen therapy on triglyceride levels in 25 menopausal women with NIDDM randomized to either placebo or CEE 0.625 mg/day for 8 weeks. Source: Friday KE, et al.2