Facts About Menopausal Hormonal Therapy

10 years after the publication of the Women’s Health Initiative trials data¹, certain facts and data have emerged that can help guide us in this so controversial an issue of Menopausal Hormonal Therapy (MHT). The following is a summary of a review published lately in the journal Menopause².

It has always been a truth that MHT is an acceptable option for treating severe early menopausal symptoms. As is the wont of these symptoms, they disappear within 10 years of menopause, thus this treatment is prudent and applicable within this time frame. Such therapy must of course be precluded in the presence of medical problems, foremost of which are blood clots, heart disease, stroke and cancer.

Estrogen replacement alone suffices for a woman who has lost her uterus, whereas progesterone therapy needs to be added for the sole purpose of prevention of endometrial cancer in those who retain theirs. If the symptoms are limited to the vulva, vagina and the bladder, topical estrogen therapy to the affected parts might be enough to soothe the symptoms.

So much is so true, and we must keep in mind that the whole controversy arose not because of questionable beneficial effects, rather, the serious consequences of MHT. Foremost in the mind of most women is the occurrence of breast cancer. The WHI trials demonstrated an increased risk of breast cancer with more than 5 years continued use of the estrogen-progesterone combination therapy. This increased risk was not present in users of estrogen-only preparations, thus suggesting a causal link of breast cancer with progesterone. The data shows that the risk is not that great and decreases after discontinuation of said replacement therapy. Estrogen, whether given alone or together with progesterone, increases the risk of thromboembolic events (TE) such as deep vein thrombosis, pulmonary embolism and stroke, but these occurrences are rare before the age of 59 years.

Thus we have come to accept that combination estrogen-progesterone MHT is proven effective in the management of early menopausal symptoms only (and not for other indications) but should be used for the shortest duration and with the lowest possible dosage. More flexibility is accorded to estrogen only therapy but similar caveats should apply whenever possible.

1. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA 2002;288(3):321-333.

2. Stuenkel CA, Gass MLS, Manson J et al. A Decade After the Women’s Health    Initiative – The Experts Do Agree. Menopause 2012;19(8):846-847.

Calcitonin for osteoporosis linked to cancer

Calcitonin-containing medicines used for long durations have been utilised for the management of osteoporosis. Now however, the European Medicines Agency (EMA) have recommended the withdrawal of the nasal spray and cautioned use of other formulations due to an increased association with cancer. In fact, it recommends that calcitonin not be used for treating osteoporosis at all. As a consequence, the remaining indications for such medicines are Paget's disease, acute bone loss from immobilisation and hypercalcaemia caused by cancer, but only on a short-term basis. The basis of this decision is a review by the agency's Committee for Medicinal Products for Human Use (CHMP) using data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources. 

The increase in cancer rates when compared to placebo is in the range of 0.7 to 2.4%. Various types of cancers are involved.

Female Sexual Dysfunction

This article by Dorothy Kammerer-Doak gives a very easy to read and concise coverage on the understanding of this subject. Recommended.

Surgery for Diabetes?

Recently, two studies were published in the New England Journal of Medicine (NEMJ) providing compelling evidence that surgical methods of achieving weight loss can lead to better control of Type 1 diabetes mellitus (T1DM). It is well established that weight loss in an obese person can show marked improvement in the control of their DM.

As we are well aware, while T1DM results from the body’s failure to produce adequate amounts of the hormone insulin, Type 2 DM (T2DM) is a consequence of improper utilization of this hormone. Regardless of the type, DM becomes more difficult to manage as it progresses and ultimately leads to serious and severe complications such as heart disease, kidney failure, blindness and stroke.

Crucial to proper management of this disease is the adequate control of blood sugar centered upon lifestyle measures that encourage weight loss and physical activity. The weight loss regimen involving diet and exercise can be a mentally and physically painful process with often a less than desirable outcome. Many patients are unable to achieve good glycemic control, leading to the addition of medications, frequently with increasing number and dosage, and ultimately the addition of insulin therapy. Counter to the aim of the therapy, one of the side effects of insulin therapy is weight gain, thus rendering management more difficult.

It is no surprise then that more patients are starting to resort to surgery to decrease the size of their stomach. This type of weight loss surgery is termed bariatric surgery and involves gastrectomy (removal of part of the stomach), stapling or banding of the stomach. Although having been around for some time now, an upsurge in cases of bariatric surgery for the management of DM has been reported, mainly due to recent information from clinical studies that showed significant weight loss and subsequent improvement in diabetic control. These recent studies provide more dependable information because of their random and rigorous comparison between medical and surgical forms of treatment. There is now better proof that weight loss operations seem to work much better than standard medical management. 

Nevertheless, caution must be employed and it may be wise to examine the studies in depth and note their deficiencies. They involved only a small number of patients (150) and were of a short duration. As well as not being able to prove long-term benefits, it is also questionable if the results of bariatric surgery will be as good in routine clinical practice, or for that matter, in patients who are not as heavy as those in the studies. Since highly skilled surgeons performed the operations in these studies, results by others may not be as good. Surgical complications can range from infections, mineral and bone deficiencies and other injuries. Furthermore, these studies compared bariatric surgery with standard medical care involving medications, when in actual fact, the comparison should have been with medical weight loss therapy (diet, exercise, behavior change and other appropriate medical interventions). Patients succeeding with medical treatment would then have no necessity to undergo surgery at all.

To be fair though, bariatric surgery has been recognized as appropriate treatment, but only for those obese patients with Type 2 DM who are unable to reach their glycaemic targets with the prescribed medical therapies.

In conclusion, we should not rush to embrace bariatric surgery as a standard treatment alternative for DM despite the strong evidence suggesting so. Due recognition has to be given for the hard work put in by the researchers, but benefit must be shown in a larger numbers of patients, and over a longer period of time before we can determine the place of bariatric surgery in the management of Type 2 DM.

References:

Schauer PR et al. Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. March 26, 2012 (10.1056/NEJMoa1200225)

Mingrone G et al. Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes. March 26, 2012 (10.1056/NEJMoa1200111)

Zimmet P, George K, Alberti MM. Surgery or Medical Therapy for Obese Patients with Type 2 Diabetes? March 26, 2012 (10.1056/NEJMe1202443)

Guidelines on epilepsy management in pregnancy

Epilepsy is a common condition affecting many women in the reproductive age group. It is estimated that about 1 million women with epilepsy in the United States are in their reproductive years. Increased fetal and maternal risks in such patients are well established. It is with this in mind that the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) published Practice Parameter Updates on the pregnant woman with epilepsy in 2009. Following are guidelines taken from that report.

The effect of antiepileptic drugs (AED)

The general worldwide incidence of major structural and genetic birth anomalies is estimated to be about 3% of births. Epileptic women taking AED during the first trimester have registered a higher incidence of such defects. This becomes quite apparent when we compare these women to those epileptics not on medication, and when we consider the effects of AED on organogenesis. Valproic acid (VPA) is shown to have a higher risk amongst the AED, with polytherapy also increasing the risk compared to monotherapy.

It is recommended that VPA be avoided especially during the first trimester, preferably preconception, if not altogether during pregnancy. Patients desiring pregnancy need to be changed to alternate therapy such as lamotrigine (LTG) or levatiracetam (LVT), which happen to be 2 of the most studied AED in pregnancy.

Increased surveillance involving detailed ultrasound scans and possibly amniocentesis are essential for these patients.

The role of Folic acid (folate)

Higher dose folic acid (about 5mg) is known to prevent neural tube defects in pregnancy, if taken at least 3 months preconceptually. Certain AED such as carbamazepine, phenytoin and even LTG lower folic acid levels and may increase the risk of neural tube defects. Although no exact evidence exists regarding the correct dosage in pregnancy, 5 mg/d of folic acid supplementation for women with epilepsy of childbearing age for 3 months prior to conception and for at least 10- to 12-weeks postconception is now the standard recommendation.

The first convulsion in pregnancy

Firstly, any convulsive event in pregnancy must be confirmed as such rather than loss of consciousness or a shaking event. Differential diagnoses include metabolic alterations and medications in the first trimester, low blood pressure and syncope in the second, and eclampsia and stroke being of more dire consequence in the third trimester and postpartum period. Mass lesions and infections can occur throughout pregnancy.

Adequate inpatient investigation includes laboratory tests, lumbar puncture, electroencephalogram (EEG) and magnetic resonance imaging (MRI) of the brain.

Once an unprovoked seizure is established, appropriate first line therapy should include enough sleep and carbamazepine or LVT depending on the seizure type. Although LTG is relatively safe, therapeutic levels are hard to achieve when started in pregnancy.

The dose of medication during pregnancy

Almost all AED levels drop during pregnancy due to increased renal clearance and hepatic elimination, but return to baseline within a few weeks of delivery. Thus, most medications require a slight dose increase once pregnancy is confirmed. LTG especially undergoes a marked drop in serum levels. Monitoring of the levels of AED should be considered.

Delivery and Postpartum

Women with well-controlled epilepsy or those seizure-free for 1 year prior to pregnancy have very little risk of a fit around the time of delivery and in the immediate postpartum period. The highest risk is with those patients with active epilepsy.

The patient should be on regular medication throughout the peripartum period and adequate rest has been shown to be beneficial. Tramadol, which is known to provoke seizures, should be avoided to further decrease the risk of an epileptic fit.

Since AED levels gradually increase back to normal postpartum, it is recommended that they be closely monitored during this period, especially in the case of LTG due to the aforementioned reason.

References

1.     Harden CL, Hopp J, Ting TY, et al. American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73(2).

2.     Cunnington MC, Weil JG, Messenheimer JA et al. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology 2011;76(21):1817–1823

3.     Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol Clin 2009;27(4):993–1002.

4.     De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. 
N Engl J Med 2007;357(2):135–142.

5.     Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. ACOG 
educational bulletin. Seizure disorders in pregnancy. Int J Gynaecol 
Obstet 1997;56(3):279-286.

6.     EURAP Study Group. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy 
pregnancy registry. Neurology 2006;66(3):354-360.

7.     Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Effects of breastfeeding in children of women 
taking antiepileptic drugs. Neurology 2010;75(22):1954–1960.