A 33-year-old woman with type 1 diabetes came to the clinic for help adjusting her insulin pump therapy. She had been on the insulin pump since shortly after her diagnosis was established 12 years earlier. She was a bright, articulate, middle-level executive in a major company and knew more about pump management than most of us, certainly more than me. She came to the clinic with her husband and their 13-month-old daughter and she had very comfortably managed her pump during pregnancy and the early hectic days of motherhood.

Earlier in the day she had seen her gastroenterologist, who had initiated therapy with prednisone (Vintage Pharms) 20 mg daily and azathioprine (Azasan, AAIPharma LLC) for treatment of autoimmune hepatitis. She has been forewarned of this regimen, which is why she had made the appointment with me, but was appropriately concerned about requiring frequent adjustments. She had been told that the azathioprine would be only a short course but that she should anticipate requiring prednisone for some time.

Together we designed changes to her insulin pump settings, made arrangements for continuous glucose monitoring (CGM) for three days, and set things in motion for her to purchase her own CGM.

When we had that all settled, she wanted to know how therapy for hepatitis would affect the treatment of her thyroid disease. The physical exam suggested she was euthyroid on her current replacement dose but I did order a thyroid-stimulating hormone test to be sure since it which had not been measured for several months.

When the result came back the next day the TSH was reported as 155 mU/L!

Autoimmune thyroid disease is a fairly common finding in type 1 diabetes and usually easy to control but between baby, work and hepatitis she had paid less attention to her thyroid medication – more often than not missing a dose. A repeat physical exam was unchanged, even knowing how hypothyroid she was and I am still struggling to explain this other than a suboptimal exam by me.

The prednisone is going to increase her insulin requirements and likely have some positive effect on the hypothyroidism (albeit not standard therapy for that). However, while she is recovering a euthyroid state her metabolic rate will be in a state of flux and glycemic control will be hard to stabilize.

The good news is that she was stunned by the TSH, has a very supportive husband and has taken a medical leave from work (working from home at her own pace with great understanding from her company) to devote the time necessary to care for herself and baby.

Three months into therapy for hepatitis she is off the azathioprine, her TSH is normal and she has had no symptomatic hypoglycemic events. Her CGM data are not so clean and it is an ongoing struggle to handle the diabetes, the prednisone and the effects of prednisone on her weight and appearance.

Now it is time to think about the skeletal effects of steroid therapy, so easily overlooked in someone with all that my patient has going on. With type 1 diabetes she is likely to have lower bone mineral density when compared with her peers, temporarily aggravated by pregnancy and lactation (bone loss during pregnancy and lactation is not trivial but is almost completely recoverable under normal circumstances). She does not really need to have a BMD test since it would not influence my intervention decision, but the insurance would not cover her therapy on the basis of history alone – sometimes they refuse coverage without a BMD even when the history includes an osteoporosis related minimal trauma fracture. Of the several options available, I selected IV ibandronate (Boniva, Roche) every three months, given as a short IV push since she is already scheduling visits to one doctor or another that frequently.

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I recently saw an 87-year-old woman with hypercalcemia due to primary hyperparathyroidism. She had previous parathyroidectomy 10 years ago for the same diagnosis with subsequent resolution of hypercalcemia. However, during the past two years her serum calcium has increased.

Most recently, serum calcium has been >11 mg/dL. Her parathyroid hormone is 183 pg/mL and 25-hydroxyvitamin D is 46 ng/mL. She is frail, weak and has been falling at home. I found several bruises over her arms and chest but she could not tell me how they got there. She could not tell me how much, or even if she was taking oral calcium supplements at home.

Indeed, after she saw me she was admitted to the hospital that afternoon for dehydration. I wonder how much of her weakness and other symptoms are related to the hypercalcemia. Once she is discharged, her primary care physician plans to admit her to an extended care facility.

The question is what to do about the hypercalcemia. With her poor health, she is obviously not a candidate for repeat parathyroidectomy. The risks of surgery would outweigh the benefits. In the past, our only option for non-surgical management of hypercalcemia would have been bisphosphonate. However, this patient also has chronic renal insufficiency with an estimated glomerular filtration rate of 30 mL/min to 35 mL/min, which means that bisphosphonate is not the best choice.

Cinacalcet (Sensipar, Amgen) is a calcium mimetic agent and is FDA approved for treatment of secondary hyperparathyroidism of renal disease and also parathyroid hormone carcinoma. However, even though it is an off-label use, cinacalcet can also be very effective for management of refractory hypercalcemia of primary hyperparathyroidism.

If this woman still has severe hypercalcemia after being rehydrated, then initiating cinacalcet will be the next step. The starting dose is 30 mg orally, once-daily and can be titrated every two to four weeks as needed. I follow calcium, phosphorus, and parathyroid hormone weekly with initiation of therapy until I am sure that a stable maintenance dose has been found. Then, I monitor less often, perhaps once per month.

One problem with cinacalcet is that it is expensive. Because it does not cure the hyperparathyroidism, it must be continued indefinitely. Thus, it should be used only when surgery is not an option. I have used cinacalcet with success in a number of patients including those who are not surgical candidates and those who have failed repeated attempts at localization and surgery. Cinacalcet is well tolerated and appears to reduce parathyroid hormone and maintain normocalcemia long-term.

Peacock M. J Clin Endocrinol Metab. 2009;94:4860-4867.

Marcocci C. J Clin Endocrinol Metab. 2009;94:2766-2772.

Peacock M. J Clin Endocrinol Metab. 2005;90:135-141.

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Over the years, several clinical trials have questioned the benefits and risks of postmenopausal hormone replacement therapy. Soon after the results of the Women’s Health Initiative were released, many women requested to have HT stopped due to concerns about the risks of such therapy. Afterwards, many felt poorly and requested therapy to be reinitiated.

Besides managing the symptoms of menopause, HT reduces postmenopausal bone loss for as long as therapy is continued. However, HT may also increase risk for breast cancer and venous thrombotic events. Concerns have been also raised about HT potentially increasing cardiovascular events. Because of this, guidelines suggest that HT be used only for short-term management of menopause symptoms and not for chronic disease prevention.

However, the issue of venous thrombosis and CV risks associated with HT continues to be an open question, as the effects of therapy may not be the same in all populations and risk may also depend on the form of HT prescribed. Some studies suggest a trend towards less progression of atherosclerosis if HT is initiated earlier in younger women who do not have risk factors or preexisting disease. Whether that will also mean fewer CV events, is not clear.

In the February issue of Arteriosclerosis, Thrombosis and Vascular Biology, researchers published results of the French E3N study which evaluated the route of HT administration with risk of idiopathic venous thrombosis. A total of 80,308 women in France were followed for an average of 10.1 years. They found that oral estradiol was associated with a 1.7-fold increased risk for venous thrombosis compared to 1.1-fold increased risk for transdermal estradiol when adjusted for other risk factors. The authors suggested that transdermal estradiol may be a safer form of HT from the perspective of risk for venous thrombosis.

One limitation of the study is that the researchers excluded provoked venous thrombosis due to identified causes and also excluded thrombotic events other than deep venous thrombosis or pulmonary embolism. They did this to avoid diluting the effects of HT on thrombosis risk. I understand why they did this, however in most patients experiencing venous thrombosis, the cause is multi-factorial.

Other studies have suggested decreased risk for venous thrombosis when using transdermal estradiol compared to oral preparations. The Estrogen and Thromboembolism Risk study, also in France, found no increase in venous thrombosis when estradiol was given transdermally but led to a fourfold increased risk when administered orally.

A meta-analysis concluded that oral estrogen is associated with a 2.5-fold increased risk but there was only a 1.2-fold increased risk with transdermal administration.

A problem with these studies is that they were observational. There may be confounders we are unaware of to explain these results. The groups studied are not identical to those we see in our practices. Therefore, we cannot be certain that results can be extrapolated to our own patient population. Nevertheless, based on our current knowledge, I tend to recommend transdermal estradiol as the probable safest route of estradiol administration in regards to risk of venous thrombosis. More research is needed, however, to confirm whether this assumption is correct and applies to all patient populations.

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