- Email: [email protected]
Premenstrual syndrome no progesterone; premenstrual dysphoric disorder no serotonin deficiency
10 O’Brien Er, Alpers CE, Stewart DK, et al. Proliferation in primary and restenotic coronary atherectomy tissue: implications for antiproliferative therapy. Circ Res 1993; 73: 223-31. 11 Mintz GS, Kovach JA, Pichard AD, et al. Geometric remodelling is the predominant mechanism of clinical restenosis after coronary angioplasty. Circulation 1994; 90: 1-24 (abstr). 12 Nunes GL, Sgoutas DS, Sigman SR, et al. Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterio Thromb 1995; 15: 156-65. 13 Tanaka H, Suzuki A, Schwatrz D, Sukhova G, Libby P. Activation of smooth muscle and endothelial cells following balloon injury. Ann N Y Acad Sci 1995; 748: 526-29. 14 Strauss BH, Chisholm RJ, Keeley FW, Gotlieb AI, Logan RA, Armstrong PW. Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circ Res 1994; 75: 650-58.
Premenstrual syndrome
no
premenstrual dysphoric serotonin deficiency
disorder
Freeman and colleagues’1 micronised progesterone
progesterone; no
lately suggested that oral is
ineffective
for
severe
premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD). In an era when PMS is still regarded and treated by many doctors as a progesteronedeficiency disease, a role for luteal-phase administration of progesterone is questionable. PMS differs from PDD.2 Essential features of PDD are symptoms such as profoundly depressed mood, anxiety, lability of affect, and decreased interest in activities. These symptoms occur during the last week of the luteal phase and are always absent in the week following menses. PDD can be distinguished from the far more common PMS by use of prospective daily ratings of symptoms and strict criteria.2 PDD differs from PMS in its characteristic pattern of complaints, their severity, and the resulting impairment. However, even the strictly defined subgroup of PDD is not homogeneous. At least 75% of women report minor or isolated premenstrual changes. Limited studies suggest an occurrence of "premenstrual syndrome" (variably defined) of 20-50%, and that 3-5% of women experience symptoms that may meet the criteria ofPDD.2 Cyclical mood changes may occur, without abnormalities of gonadal steroid concentrations,3 during the luteal phase in ovulatory cycles and in hysterectomised women with intact ovarian activity. The mood changes disappear when the incoming progesterone tide is abolished naturally (menopause) or artificially (castration, gonadotropin releasing hormone analoguesS). Once the incoming tide of progesterone has set the process in motion, the sequence of events cannot be disrupted at a later stage-eg, by the administration of the anti-progestagen mifepristone during the luteal phase.6 Thus luteal-phase administration of progesterone cannot be expected to be of any use, and oral administration of even high doses of micronised progesterone during the luteal phase is ineffective in reducing PMS.1 These observations accord with the results of progesterone 7
suppository treatment. Why are some women more prone to cyclical mood changes than others? We need to know what determines their susceptibility, what colours their mood, and what pathways and neurotransmitters
are involved. Serotonin, which has a role in behaviour and mood changes, might play a part, or there might be an enzyme deficiency or
inborn error of metabolism in susceptible In this connection, psychotropic agents have lately been tested. Alprazolam, a benzodiazepine with anxiolytic, antipanic, and some antidepressant properties, offers a therapy limited to the luteal phase.’ However, the results are not robust. Using a stringent clinical definition of 50% improvement in total symptom scores, Freeman et al’ found that 37% of women in the alprazolam group improved from baseline compared with 29% in the oral progesterone group and 30% in the placebo group. In view of the narrow margin of effectiveness of alprazolam in this large sample, it is not surprising that small samples produce conflicting results. And how can one explain the large group who have no response to alprazolam? The data could indicate that the effect of alprazolam comes about via pathways that have no relation to PMS. In another recent study, Steiner and colleagues8 showed that continuous administration of fluoxetine, an antidepressant that selectively inhibits the reuptake of serotonin, is useful in the treatment of PDD. 52% of the women receiving fluoxetine compared with 22% of those receiving placebo had an improvement of 50% in their first cycle. Here again it is difficult to account for the large group (48%) who had no response to fluoxetine. One explanation is that PDD too is not homogeneous so an improvement of the whole group of PDD with a serotonin reuptake inhibitor cannot be expected. Finally, I wonder why the researchers did not comment on one aspect of their data-a considerable drop in improvement from about 55% to 37% after three cycles. The weakly positive results with alprazolam1 may result from influencing pathways that have no immediate causal relation with PMS. Furthermore, in the alprazolam study, patients with PMS were treated, as well as those with PDD. In addition, different scales were used in the alprazolam and fluoxetine studies, so the studies are not comparable. The results of the fluoxetine studyS indicate that, within the non-homogeneous group with PDD, there is a subgroup showing improvement with this serotonin reuptake inhibitor. Here again it is clear that these positive results and the considerable percentage of patients with PDD who do not respond to fluoxetine do not accord with a causal relation between serotonin and PDD. What can we learn for clinical practice from these randomised trials? Depressed mood, anxiety, affective lability, and decreased interest in activities occurring later in the chain of events cannot be influenced by progesterone but can be partly alleviated in some cases either by the benzodiazepine alprazolam or by a specific serotonin reuptake inhibitor such as fluoxetine, which have entirely different mechanisms of action. We cannot conclude that PDD is a serotonin deficiency disease. So far, abolishing the initial triggering effect of the incoming tide of progesterone is the most effective treatment of severe PMS and PDD. Further progress depends on discovering what the tide sets in motion at a central level. even
an
women.
Huub A I M van Leusden Department of Obstetrics and Gynaecology, Ziekenhuis Rijnstate, Arnhem, Netherlands 1
Freeman EW, Rickels K, Sondheimer SJ, Polansky M. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 1995; 274: 51-57.
1443
2 3 4
5 6
1981; 88: 530-36. Hussain SY, Massil JH, Matta WH, Shaw RW, O’Brien PM. Buserelin in premenstrual syndrome. Gynecol Endocrinol 1992; 6: 57-64. Schmidt PJ, Nieman LK, Grover GN, Muller KL, Merriam GR, Rubinow DR. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Engl J Med 1991; 324: 1174-79.
7
8
long-term complication of lymphangiosarcoma is, fortunately, uncommon. Poor axillary surgery followed by radiotherapy results in an increased lymphoedema rate, but medical oncologists have their own ways of causing arm dysfunction, via drug finalised. The
Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994: 715-18. Rubinow DR, Schmidt PJ. Premenstrual syndrome: a review of endocrine studies. The Endocrinologist 1992; 2: 47-54. Backstrom T, Boyle LT, Baird DT. Persistence of symptoms of premenstrual tension in hysterectomized women. Br J Obstet Gynaecol
Freeman E, Rickels K, Sondheimer SJ, Polansky M. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA 1990; 264: 349-53. Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. N Engl J Med 1995; 332: 1529-34.
Upper
limb disease in
breast
cancer
women
treated for
Adjuvant radiotherapy for early breast
cancer reduces the risk of local recurrence and it may improve overall survival. This benefit is not achieved without some cost. Acute local problems such as desquamation and erythema are short-lived but the excess of cardiac mortality found in treatment of left-sided breast cancers due to irradiation of the anterior descending coronary artery was more serious, especially since it was insidious in onset and was not appreciated for many years. A recent report in the British Journal of Surgery adds to knowledge on radiationinduced arterial damage. Taylor et al’ used doppler ultrasonography, pulse volume recording, and venous outflow plethysmography to demonstrate arterial disease in the upper limb, and found it in 22% of patients given radiotherapy compared with 4% of those receiving surgery alone. The radiotherapy patients were recruited from a cohort treated 15-19 years previously in a cobalt unit. Pain, weakness, numbness, and paraesthesiae were also more common in irradiated limbs; some of these symptoms were attributed to other radiation-induced effects such as brachial plexopathy or arthritis. The histological changes in arteries seen after radiotherapy progress from early endothelial disruption, medial and adventitial damage, and periarterial fibrosis to accelerated
atherosclerosis.
Radiotherapy is not the only form of treatment to affect arm function. Surgery can also be injurious if done badly or inappropriately. The arm of an anaesthetised patient is vulnerable and gets in the way during an operation. The immediate complications include nerve damage (the thoracodorsal and long thoracic nerves should be seen and preserved; the intercostobrachial is often divided but should be spared wherever possible) in addition to vascular damage, seromas, and frozen shoulder. Sympathetic dystrophy is a rare complication but lymphoedema is enough of a problem that UK revised guidelines on prevention and treatment have been
1444
subclavian and/or innominate extravasations and thrombosis after insertion of Hickman-type infusion lines. These complications can be reduced by skilled insertion of the lines, and one suggestion is that percutaneous insertion by an interventional radiologist is required3-but where are we to find enough of these specialists? So how can we reduce the arm complications seen after treatment of breast cancer? Avoidance of venesection and intravenous cannulation of the arm at risk along with careful padding peroperatively are a start. Local agreement with the clinical oncologist as to axillary management should precede surgical intervention. Meticulous axillary surgery requires manipulation of the arm to allow full access to the upper axilla and identification and preservation of the thoracodorsal and long thoracic nerves, as well as the intercostobrachial whenever possible. The axillary artery and brachial plexus are not routinely visualised but the vein is a landmark to the dissection and is thus potentially vulnerable. Drainage of the inevitable seroma with low-powered suction and early mobilisation of the shoulder with exercises taught preoperatively reduce the incidence of frozen shoulder. Adjuvant chemotherapy should be administered via the opposite arm, and long-saphenous access to the central venous system should be considered if a long-term catheter is to be used. Radiotherapy may not always be indicated: small, well-differentiated carcinomas may, for example, be treated by excision and tamoxifen. In the UK the BASO II trial is recruiting patients to answer this question. If the axilla is involved, many forward-thinking clinical oncologists prefer a surgical clearance, confining radiotherapy to the remaining breast and, perhaps, the supraclavicular fossa and neck. Radiotherapy often has to be timed to fit in with courses of chemotherapy. The patient should be warned of the risks of lymphoedema and given advice on care of the hand postoperatively, and someone with experience of managing lymphoedema should be available to the breast unit. Guidelines on the management of adverse effects following breast radiotherapy have just been published by the UK’s Royal College of Radiologists. Richard Sainsbury Royal Infirmary, Huddersfield, 1 2
3 4
UK
Taylor PJ, Cooper GG, Sarkar TK. Upper-limb disease in women treated for breast cancer. Br J Surg 1995; 82: 1089-91. Janse AJ, van Coevorden F, Peterse H, Keus RB, van Dongen JA. Lymphedema-induced lymphangiosarcoma. Eur J Surg Oncol 1995; 21: 155-58. Adam A. Insertion of long term central venous catheters: time for a new look. BMJ 1995; 311: 341-42. Maher Committee. Management of adverse effects following breast radiotherapy. London: Royal College of Radiologists, 1995.
Premenstrual syndrome
no
premenstrual dysphoric serotonin deficiency
disorder
Freeman and colleagues’1 micronised progesterone
progesterone; no
lately suggested that oral is
ineffective
for
severe
premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD). In an era when PMS is still regarded and treated by many doctors as a progesteronedeficiency disease, a role for luteal-phase administration of progesterone is questionable. PMS differs from PDD.2 Essential features of PDD are symptoms such as profoundly depressed mood, anxiety, lability of affect, and decreased interest in activities. These symptoms occur during the last week of the luteal phase and are always absent in the week following menses. PDD can be distinguished from the far more common PMS by use of prospective daily ratings of symptoms and strict criteria.2 PDD differs from PMS in its characteristic pattern of complaints, their severity, and the resulting impairment. However, even the strictly defined subgroup of PDD is not homogeneous. At least 75% of women report minor or isolated premenstrual changes. Limited studies suggest an occurrence of "premenstrual syndrome" (variably defined) of 20-50%, and that 3-5% of women experience symptoms that may meet the criteria ofPDD.2 Cyclical mood changes may occur, without abnormalities of gonadal steroid concentrations,3 during the luteal phase in ovulatory cycles and in hysterectomised women with intact ovarian activity. The mood changes disappear when the incoming progesterone tide is abolished naturally (menopause) or artificially (castration, gonadotropin releasing hormone analoguesS). Once the incoming tide of progesterone has set the process in motion, the sequence of events cannot be disrupted at a later stage-eg, by the administration of the anti-progestagen mifepristone during the luteal phase.6 Thus luteal-phase administration of progesterone cannot be expected to be of any use, and oral administration of even high doses of micronised progesterone during the luteal phase is ineffective in reducing PMS.1 These observations accord with the results of progesterone 7
suppository treatment. Why are some women more prone to cyclical mood changes than others? We need to know what determines their susceptibility, what colours their mood, and what pathways and neurotransmitters
are involved. Serotonin, which has a role in behaviour and mood changes, might play a part, or there might be an enzyme deficiency or
inborn error of metabolism in susceptible In this connection, psychotropic agents have lately been tested. Alprazolam, a benzodiazepine with anxiolytic, antipanic, and some antidepressant properties, offers a therapy limited to the luteal phase.’ However, the results are not robust. Using a stringent clinical definition of 50% improvement in total symptom scores, Freeman et al’ found that 37% of women in the alprazolam group improved from baseline compared with 29% in the oral progesterone group and 30% in the placebo group. In view of the narrow margin of effectiveness of alprazolam in this large sample, it is not surprising that small samples produce conflicting results. And how can one explain the large group who have no response to alprazolam? The data could indicate that the effect of alprazolam comes about via pathways that have no relation to PMS. In another recent study, Steiner and colleagues8 showed that continuous administration of fluoxetine, an antidepressant that selectively inhibits the reuptake of serotonin, is useful in the treatment of PDD. 52% of the women receiving fluoxetine compared with 22% of those receiving placebo had an improvement of 50% in their first cycle. Here again it is difficult to account for the large group (48%) who had no response to fluoxetine. One explanation is that PDD too is not homogeneous so an improvement of the whole group of PDD with a serotonin reuptake inhibitor cannot be expected. Finally, I wonder why the researchers did not comment on one aspect of their data-a considerable drop in improvement from about 55% to 37% after three cycles. The weakly positive results with alprazolam1 may result from influencing pathways that have no immediate causal relation with PMS. Furthermore, in the alprazolam study, patients with PMS were treated, as well as those with PDD. In addition, different scales were used in the alprazolam and fluoxetine studies, so the studies are not comparable. The results of the fluoxetine studyS indicate that, within the non-homogeneous group with PDD, there is a subgroup showing improvement with this serotonin reuptake inhibitor. Here again it is clear that these positive results and the considerable percentage of patients with PDD who do not respond to fluoxetine do not accord with a causal relation between serotonin and PDD. What can we learn for clinical practice from these randomised trials? Depressed mood, anxiety, affective lability, and decreased interest in activities occurring later in the chain of events cannot be influenced by progesterone but can be partly alleviated in some cases either by the benzodiazepine alprazolam or by a specific serotonin reuptake inhibitor such as fluoxetine, which have entirely different mechanisms of action. We cannot conclude that PDD is a serotonin deficiency disease. So far, abolishing the initial triggering effect of the incoming tide of progesterone is the most effective treatment of severe PMS and PDD. Further progress depends on discovering what the tide sets in motion at a central level. even
an
women.
Huub A I M van Leusden Department of Obstetrics and Gynaecology, Ziekenhuis Rijnstate, Arnhem, Netherlands 1
Freeman EW, Rickels K, Sondheimer SJ, Polansky M. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 1995; 274: 51-57.
1443
2 3 4
5 6
1981; 88: 530-36. Hussain SY, Massil JH, Matta WH, Shaw RW, O’Brien PM. Buserelin in premenstrual syndrome. Gynecol Endocrinol 1992; 6: 57-64. Schmidt PJ, Nieman LK, Grover GN, Muller KL, Merriam GR, Rubinow DR. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Engl J Med 1991; 324: 1174-79.
7
8
long-term complication of lymphangiosarcoma is, fortunately, uncommon. Poor axillary surgery followed by radiotherapy results in an increased lymphoedema rate, but medical oncologists have their own ways of causing arm dysfunction, via drug finalised. The
Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994: 715-18. Rubinow DR, Schmidt PJ. Premenstrual syndrome: a review of endocrine studies. The Endocrinologist 1992; 2: 47-54. Backstrom T, Boyle LT, Baird DT. Persistence of symptoms of premenstrual tension in hysterectomized women. Br J Obstet Gynaecol
Freeman E, Rickels K, Sondheimer SJ, Polansky M. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA 1990; 264: 349-53. Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. N Engl J Med 1995; 332: 1529-34.
Upper
limb disease in
breast
cancer
women
treated for
Adjuvant radiotherapy for early breast
cancer reduces the risk of local recurrence and it may improve overall survival. This benefit is not achieved without some cost. Acute local problems such as desquamation and erythema are short-lived but the excess of cardiac mortality found in treatment of left-sided breast cancers due to irradiation of the anterior descending coronary artery was more serious, especially since it was insidious in onset and was not appreciated for many years. A recent report in the British Journal of Surgery adds to knowledge on radiationinduced arterial damage. Taylor et al’ used doppler ultrasonography, pulse volume recording, and venous outflow plethysmography to demonstrate arterial disease in the upper limb, and found it in 22% of patients given radiotherapy compared with 4% of those receiving surgery alone. The radiotherapy patients were recruited from a cohort treated 15-19 years previously in a cobalt unit. Pain, weakness, numbness, and paraesthesiae were also more common in irradiated limbs; some of these symptoms were attributed to other radiation-induced effects such as brachial plexopathy or arthritis. The histological changes in arteries seen after radiotherapy progress from early endothelial disruption, medial and adventitial damage, and periarterial fibrosis to accelerated
atherosclerosis.
Radiotherapy is not the only form of treatment to affect arm function. Surgery can also be injurious if done badly or inappropriately. The arm of an anaesthetised patient is vulnerable and gets in the way during an operation. The immediate complications include nerve damage (the thoracodorsal and long thoracic nerves should be seen and preserved; the intercostobrachial is often divided but should be spared wherever possible) in addition to vascular damage, seromas, and frozen shoulder. Sympathetic dystrophy is a rare complication but lymphoedema is enough of a problem that UK revised guidelines on prevention and treatment have been
1444
subclavian and/or innominate extravasations and thrombosis after insertion of Hickman-type infusion lines. These complications can be reduced by skilled insertion of the lines, and one suggestion is that percutaneous insertion by an interventional radiologist is required3-but where are we to find enough of these specialists? So how can we reduce the arm complications seen after treatment of breast cancer? Avoidance of venesection and intravenous cannulation of the arm at risk along with careful padding peroperatively are a start. Local agreement with the clinical oncologist as to axillary management should precede surgical intervention. Meticulous axillary surgery requires manipulation of the arm to allow full access to the upper axilla and identification and preservation of the thoracodorsal and long thoracic nerves, as well as the intercostobrachial whenever possible. The axillary artery and brachial plexus are not routinely visualised but the vein is a landmark to the dissection and is thus potentially vulnerable. Drainage of the inevitable seroma with low-powered suction and early mobilisation of the shoulder with exercises taught preoperatively reduce the incidence of frozen shoulder. Adjuvant chemotherapy should be administered via the opposite arm, and long-saphenous access to the central venous system should be considered if a long-term catheter is to be used. Radiotherapy may not always be indicated: small, well-differentiated carcinomas may, for example, be treated by excision and tamoxifen. In the UK the BASO II trial is recruiting patients to answer this question. If the axilla is involved, many forward-thinking clinical oncologists prefer a surgical clearance, confining radiotherapy to the remaining breast and, perhaps, the supraclavicular fossa and neck. Radiotherapy often has to be timed to fit in with courses of chemotherapy. The patient should be warned of the risks of lymphoedema and given advice on care of the hand postoperatively, and someone with experience of managing lymphoedema should be available to the breast unit. Guidelines on the management of adverse effects following breast radiotherapy have just been published by the UK’s Royal College of Radiologists. Richard Sainsbury Royal Infirmary, Huddersfield, 1 2
3 4
UK
Taylor PJ, Cooper GG, Sarkar TK. Upper-limb disease in women treated for breast cancer. Br J Surg 1995; 82: 1089-91. Janse AJ, van Coevorden F, Peterse H, Keus RB, van Dongen JA. Lymphedema-induced lymphangiosarcoma. Eur J Surg Oncol 1995; 21: 155-58. Adam A. Insertion of long term central venous catheters: time for a new look. BMJ 1995; 311: 341-42. Maher Committee. Management of adverse effects following breast radiotherapy. London: Royal College of Radiologists, 1995.