Can sildenafil (Viagra) be used in women?
By Denis Bélanger
This question has been hotly debated. The drug has been studied almost exclusively in men and is currently approved in Canada only for use in men. Currently, there is very little clinical literature that documents the effects of sildenafil in women.
One of the biggest problems to overcome, before initiating research on the effects of sildenafil on women, is the question of how to measure arousal in women.1 This is particularly difficult because relatively little is known about sexual functioning and dysfunction in women.1 The clitoris in the female is the equivalent of the penis in the male, as both become engorged with blood during sexual arousal. Sildenafil acts by enhancing the effects of nitric oxide, released by the body during sexual stimulation.2 Nitric oxide relaxes the smooth muscles and dilates the blood vessels in the penis, leading to an erection. Specialists believe that sildenafil would have similar effects in the smooth muscles and blood vessels of the vagina.2
The effects of sildenafil were examined in a small study of 22 women aged 25 to 41, who suffered from diminished sex-ual sensation, poor lubrication, and difficulty in achieving orgasm.2 The reasons for their sexual dysfunction included hysterectomy or other pelvic surgery, diabetes and hypertension. The women in the study had positive responses to sildenafil (dose not specified), which included being able to achieve orgasm.2 Similar side effects were reported to those seen in men.2
Another randomized study of sildenafil in 33 postmenopausal women failed to show improvement in sexual desire or intercourse satisfaciton. Each woman took sildenafil 50 mg about one hour prior to planned sexual activity for a 12-week period (mean of three doses per week).3
In summary, there is currently too little data to establish whether sildenafil is safe and effective in women. One small study has indicated that women may benefit from the drug, but further research is needed before any conclusions can be made.
1. Kolata G. New drug for impotence raises hope for its use by women, too. The New York Times, April 4, 1998.
2. White K. Boston university testing Viagra in women with sexual dysfunction. J Women’s Health 1998;7:795-6.
3. Anon. Viagra offers little benefit to women, say researchers. Doctor’s guide to medical and other news. http://www.pslgroup.com/dg/eacc.2.htm (accessed March 8, 1999).
Why would a cardiologist prescribe
folic acid and vitamin B12?
The answer to this question can be simply summarized in one word–hyperhomocysteinemia (HHC). This condition has recently been identified as an important risk factor for atherosclerotic vascular disease.1,2 HHC can be detected in up to 30 per cent of patients with coronary heart disease and 42 per cent of patients with cerebrovascular disease.3
Homocysteine is an amino acid intermediate of the essential amino acid methionine. The average American diet contains about 2 g methionine per day. The recommended daily allowance of methionine is 0.9 g.3 The excess methionine is converted to homocysteine via enzymatic transmethylation. Homocysteine is then converted to cystathionine by a vitamin B6 dependent pathway.3 Cystathionine is converted to cysteine, which is eventually degraded and excreted in the urine. Homocysteine is also recycled back to methionine by two pathways. The most important pathway requires vitamin B12 and folate, while the minor pathway requires betaine as a cofactor.3
Causes of HHC: There are several causes of HHC, including deficiencies of any of the enzymes and cofactors (e.g., folic acid, vitamin B6, vitamin B12) involved in homocysteine metabolism, and chronic diseases such as renal dysfunction, systemic lupus erythematosus, malignant neoplasm and psoriasis.1 Advanced age and smoking have also been identified as risk factors.1 Men tend to have a higher homocysteine serum level compared to women.1 The use of certain medications (e.g., methotrexate, phenytoin, carbamazepine, thiazide diuretics, nicotinic acid, theophylline and colestipol) has also been associated with an increase in homocysteine.1
Harmful effects of HHC: There are several hematologic and vascular abnormalities associated with HHC that contribute to an atherosclerotic and thrombotic state. HHC has been associated with endothelial cell injury (the first step in the development of atherosclerosis), increased platelet aggregation, and abnormalities in the clotting factors.3 Increased platelet aggregation is caused by an increased production of thromboxane A2 and a decreased production of prostacyclin.3 In terms of clotting factors, there is an activation of factors V, X and XII, and an inhibition of antithrombin III and factor C (natural anticoagulants).3 High homocysteine levels have also been correlated with an increase in fibrinogen levels and enhanced binding of fibrin to lipoprotein(a)–indicators of increased clotting.1
Several studies have shown a strong association between HHC and coronary artery disease, cerebrovascular disease and peripheral arterial vascular disease. One of the first studies established an overall odds ratio of 1.39 for HHC and atherosclerotic vascular disease.4 In the Physicians’ Health Study, 14,916 male physicians were followed for five years. A significantly higher plasma homocysteine level was found in the 271 patients who suffered a myocardial infarction during this period compared to healthy controls.5 In a British study, which followed 5,661 men for up to 13 years, plasma homocysteine levels were higher in the 109 patients who suffered a stroke as compared to controls.6 The recently published European Concerted Action Project attempted to identify the risks associated with HHC and conventional risk factors for atherosclerotic vascular disease.7 Patients with a homocysteine level greater than 12 µmol/L had a relative risk of 2.2 for atherosclerotic vascular disease, compared to patients with a homocysteine level below 12 µmol/L. The relative risk continued to increase with increasing homocysteine levels. The overall risk for atherosclerotic vascular disease was 1.3 for men and 1.4 for women, for every 5 µmol/L increase in total plasma homocysteine levels.
There is also a clear association between coronary artery disease and decreasing folate, vitamin B6 and vitamin B12 levels.1 The evidence of the association between coronary artery disease and vitamin B6 and vitamin B12 levels is less consistent than the evidence for folate levels.1
Normal levels of homocysteine: The currently accepted normal range for fasting homocysteine is 5-15 µmol/L. However, based on the results of the European Concerted Action Project, many specialists believe that the upper acceptable limit should be reduced to 12 µmol/L.1
Therapy for HHC: Data from clinical trials evaluating the potential benefits of homocysteine-lowering therapy are not yet available. However, the current goals for treating patients with HHC are to lower the homocysteine level to 14 µmol/L or less in primary prevention, and 11 µmol/L or less in secondary prevention.1 Daily folic acid doses of 400 µg or greater have reduced homocysteine levels by 30-42 per cent.8 Lower folic acid doses, however, did not produce a sustained significant reduction.8 Vitamin B12 supplementation also produced reductions in plasma homocysteine levels of 15 per cent.8 Vitamin B6 supplementation does not significantly lower homocysteine levels in the absence of vitamin B6 deficiency.8
Current dosing recommendations suggest initiating patients with HHC on a daily folic acid dose of 400-1,000 µg, plus a multivitamin that contains at least 400 µg folic acid.1 Homocysteine levels should be monitored at six- to eight-week intervals. Folic acid doses can be increased at these intervals in a step-wise approach, up to a maximal dose of 5 mg per day.1 If HHC persists, vitamin B12 supplementation (400 µg/day) is recommended, even in the absence of vitamin B12 deficiency.1
1. Stein JH, McBride PE. Hyperhomocysteinemia and atherosclerotic heart disease: pathophysiology, screening and treatment. Arch Intern Med 1998;158:1301-6.
2. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042-50.
3. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-27.
4. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-55.
5. Stampler MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-81.
6. Perry IJ, Refsum HM, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395-8.
7. Graham I, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project. JAMA 1997; 277:1775-81.
8. Ubbink JB, Vermaak WJH, van der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927-33.
DENIS BÉLANGER, B.Sc.Phm., is a drug information specialist at the Ottawa Valley Regional Drug Information Service in Ottawa, ON