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Menopause International 2009; 00: 1–2. DOI: 10.1258/mi.2009.009019 Why are physicians reluctant to useestrogens for anything – or do theyprefer ‘PROFOX’? London PMS and Menopause Clinic, London, UK Correspondence: Professor John Studd, London PMS & Menopause Clinic, 46 Wimpole Street, London W1G8SD, UK.
Email: [email protected] Estrogens to physicians appear to be as garlic is to Dracula antidepressants. The depression became cyclical as PMS as and equally illogical. The reluctance for bone physicians the periods returned. As they moved into their 40s, the to use estrogens for low bone density and for psychiatrists PMS that had never been adequately treated became to use transdermal estrogens for hormone responsive worse as the cyclical depression became more continuous depression is hard to understand and is a matter of great with fewer good days a month. Being in good mood concern. This objection is not new as it antedated the during their pregnancies followed by PND and PMS is the 2002 Women’s Health Initiative (WHI) study and the clue that hormonal fluctuations are a major part of the equally suspect Million Women Study by many years; aetiology of depression in women and most importantly however, these data are now used for justification for their that elevation of plasma oestradiol levels will improve the choice of medication. Even general practitioners formerly enthusiastic about hormone replacement therapy (HRT) These women respond to moderately high-dose trans- have been hobbled by outdated views from advisory dermal oestradiol at all three stages of their depression; bodies and will prescribe only for the severest of vaso- postnatal,4 premenstrual5 and perimenopausal6,7 but all motor or atrophy symptoms in the lowest dose and the too often they are neglected or treated with a range of antidepressants or mood-stabilizing drugs. The younger It would seem logical that a 50–60-year-old woman women thus suffer years of dysfunctional depression. It is with hot flushes, tiredness, depression, loss of libido, astonishing how often women with a diagnosis of bipolar pelvic atrophy and low bone density should have estro- depression become normal when their severe PMS is gens in a dose appropriate for the pathology, but this is treated by suppression of ovulation. Psychiatrists are not not happening. The fortunate few may have such treat- aware of the effect of estrogens on depression in spite ment with relief of these symptoms and a substantial of relevant publications of randomized controlled trials.
decrease in fracture risk as they have a 10–20% increase Unfortunately, these studies have not been repeated in bone density after 5–10 years of estrogens. But the by those most involved in the mental heath of women majority of these women will either have no treatment because psychiatrists do not seem to be interested in or receive antidepressants or bisphosphonates depending hormonal therapy and the pharmacological companies on which specialist clinic she is referred to.
have little desire to fund head-to-head studies of Selective serotonin reuptake inhibitors (SSRIs) of their profitable inpatent antidepressants against cheap doubtful value are used for depression and also hot estrogens. Women therefore suffer from this territorial flushes regardless of their effects on libido, mental acuity, memory, general wellbeing, weight gain and the increas- Are things better with osteoporosis? In June 2009 there ing problem of long-term dependency. These drugs also is a major three-day international meeting on osteoporo- have a deleterious effect on bone density1 even more than sis in Manchester run by the National Osteoporosis does depression untreated with SSRIs.2 It is commonplace Society without a single plenary lecture on the role of to see depressed perimenopausal women who have a estrogens. There may be a few free communications but longstanding history of premenstrual depression (PMS), there are no hormone companies involved and no interest postnatal depression (PND) who will say that they were from the bone physicians or rheumatologists on the last well without depression many years ago when they scientific committee, Hence the most effective, cheapest were last pregnant. They then had many months of and probably safest long-term treatment will not feature.
PND and was either undiagnosed or treated with How else will these specialists learn the simple skills of Menopause International Vol. 00 No. 0 Month 2009 J Studd Why are physicians reluctant to use estrogens for anything hormone therapy? The programme committee have not There is no doubt that HRT is effective in reducing the responded to protests about this omission, which is the number of osteoporotic fractures but is it safe? The initial equivalent to failing to discuss angiotensin-converting 2002 WHI study reported an increase in major side-effects enzyme inhibitors in a meeting on hypertension.
due to wrong patients of the wrong age given the wrong Not only do estrogens produce a dose-dependent and dose of an inappropriate continuous estrogen/progesto- duration-dependent increase in bone density and bone gen HRT preparation. It is little consolation to stress that architecture, but the cancellous bone collagen is also the investigators were informed of this about 15 years ago.
increased,8 leading to increased strength and fracture However, it is now clear that this preparation caused no protection. It should be noted that HRT is the only harm if started within 10 years of the menopause. It is treatment that has been demonstrated to produce fewer also re-assuring that hysterectomized patients in this age hip and vertebral osteoporotic fractures in low-risk group receiving estrogen alone have a substantial decrease and mid-risk women. The generalized increase in skin in heart attacks, breast cancer and deaths,14 although the and bone collagen that occurs when postmenopusal study of this age group was discontinued prematurely women take estrogens is also seen in the intervertebral without significance being confirmed or otherwise.15 discs. The protective cushion of the discs make up 25% No convincing explanation has been given.
of the length of the vertebral column but decreases with The increasing awareness of the safety of HRT on the age. Estrogens prevent this shrinkage, bisphosphonates cardiovascular system as featured in a IMS meeting in January is discussed by Stevenson in an accompanying My view is that estrogens should be the first choice for editorial in this edition of Menopause International.16 the prevention and treatment of low bone density in theunder 60s.10 Claus Christianson in a personal communi- cation goes further believing that they should be the first,second and third choice in this age group. Consideringthe poor efficacy, long-term side effects and cost ofthe non-hormonal preparations, it is hard to disagree.
But they may cause vaginal bleeding that seems to be another garlic moment for physicians as they feel unableto cope with it. The irony is that many bone physicians 1 Williams LJ, Pasco JA, Jacko FN, Henry MJ, Dodd S, Berk M.
who have little knowledge of estrogen therapy would Depression and bone metabolism. A review. Psychother Psychom2009;78:16–25 regard themselves as endocrinologists.
2 Vestergaard P, Rejnmark L, Mosekinlde J. Anxiiolytics, anti- Bisphosphonates are now the first-line treatment in depressants and the risk of fracture. Osteoporos Int 2006;17:807–16 spite of increasing anxiety about osteonecrosis of the 3 Studd J, Panay N. Hormones and depression in women.
jaw,11 mid-shaft femoral fractures and abnormal histo- 4 Gregoire A, Kumar R, Everitt B, Henderson AF, Studd JW.
morphometric changes in the bone.12 There is perhaps a Transdermal oestrogen treatment of severe postnatal depression.
more serious problem, if that is possible. Oesophageal and stomach symptoms are so common that 30% of women 5 Watson NR, Studd JW, Savvas M, Garnett T, Baber RJ. Treatment taking oral bisphosphonates require proton pump of severe premenstrual syndrome with oestradiol patches and inhibitor (PPI) therapy for ‘heartburn’. These are the cyclical oral norethisterone. Lancet 1989;2:730–2 6 Montgomery JC, Appleby L, Brincat M, et al. Effect of oestrogen drugs that reduce bone density and have been reported and testosterone implants on psychological disorders in the to significantly increase osteoporotic hip fractures after 7 Schmidt PJ. Mood, depression, and reproductive hormones in the Fosamax once weekly now in generic form is inexpen- menopausal transition. Am J Med 2005;118(Suppl 12B):54–8 8 Khastgir G, Studd JWW, Holland N. Anabolic effect of long-term sive and therefore being recommended by the National estrogen replacement on bone collagen in elderly postmeno- Institute of Clinical Excellence, an organization that pausal women with osteoporosis. Osteoporos Int 2001;12:465–70 still has not reported on HRT for the prevention and 9 Muscat Baron Y, Brincat M, Galea R, Calleja N. Low intervertebral treatment of osteoporosis. The other generic preparation disc height in postmenopausal women with osteoporotic prescribed frequently to post-menopausal women is vertebral fractures compared to hormone-treated and untreatedpostmenopausal women and premenopausal women without Prosac, which is already being used in combination with fosamax as a post-HRT nightmare, which could be called 10 Studd JW. Estrogens should be first choice in the prevention and PROFOX (PROzac þ FOsamaX). This substitute for estro- treatment of osteoporosis in women under the age of 60.
gens would have a deleterious effect on mood, memory, 11 Basu N, Reid DM. Bisphosphonate-associated osteonecrosis of the libido, upper gastrointestinal symptoms requiring PPI treatment and more hip fractures with little or no 12 Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast improvement of the hormone responsive symptoms that formation and long-term oral bisphosphonate therapy. N Engl trouble 50–60-year-old women. Moving from Bram Stoker’s Dracula to Mary Shelley’s monster, we must be beware that 13 Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD.
Use of proton pump inhibitors and risk of osteoporosis-related this created Frankeinstein drug does not become a feature of the treatment of middle-aged women. In combination, 14 Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, PROFOX will produce more problems in combination than Black H. Women’s Health Initiative Steering Committee. Effects of the individual components and either option is less effec- conjugated equine estrogen in postmenopausal women withhysterectomy: the Women’s Health Initiative randomized tive in well-selected patients than oestradiol perhaps with controlled trial. JAMA 2004;291:1701–12 the addition of testosterone and a short monthly course of 15 Studd J. Hysterectomy – a life-saving as well as a life-enhancing a progestogen in women with a uterus.
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