Brttiik MuHcal BuUtm (1991) VoL 48, No. 2, pp. 356-367 © The Brltiih Council 1992
Hormone replacement therapy and other menopause associated conditions D H Barlow Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Maternity Hospital, Oxford, UK
In Britain a large majority of the women who use Hormone Replacement Therapy (HRT) use it in order to alleviate symptoms thought to relate to the menopause. These include vasomotor instability, 'minor' psychological disturbance and sexual difficulties. Other HRT effects gained by the women include effects on maintainence of collagen, as in the skin, and on oestrogen sensitive tissues related to the lower urinary tract.
This volume devotes considerable space to the effect of hormone replacement therapy (HRT) on the potential prevention of some major health problems of older women, namely osteoporosis and its consequences, coronary artery disease and stroke. This is a correct emphasis since the potential health benefit for the population is considerable. However as a specialist working in the menopause field I have the strong impression that a large majority of HRT prescribing is aimed at the alleviation of menopause related symptomatology. In a recent survey of menopause related consultations in Oxford General Practice we found that a very large majority related to symptomatic complaints.1 HRT AND VASOMOTOR SYMPTOMATOLOGY Hot flushes and sweats are the commonest menopausal symptom complex2'3 and are particularly common where oestrogen withdrawal has been acute as at the surgical menopause.4
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Women know that the menopause brings flushes and generally cope if they are not too frequent. Unfortunately for some women the frequency is so high that life can be dominated by them. If the problem was always of short duration, again it might be easier to cope but 10% may still be having flushes into their sixties.5 Flushing and sweating attacks are clearly a menopausal problem and were shown to peak significantly during the climacteric years.6 They appear to correlate with the decline in oestrogen and eventually stabilise in the years of hypo-oestrogenism. Women who are experiencing intermittent oestrogenisation in the perimenopause may experience flushing despite being reasonably oestrogenised much of the time. Women treated with oestradiol implants may report flushes during the phase of relative oestrogen decline when an implant is clinically 'wearing off' despite circulating oestradiol levels comfortably in the premenopausal range. Despite these correlates with declining oestrogen studies comparing circulating oestrogen levels in those who flush and asymptomatic women do not discover a significant correlation between flushing and the oestrogen level.7 There have been apparent correlations between endocrine parameters and flushes but so far they have not provided us with a good understanding of the mechanism underlying this common symptom. An early idea was that gonadotrophin levels might correlate with flushing8 but this was not confirmed. Study of the acute flush episode with frequent blood sampling then revealed pulses of luteinising hormone (LH) coincident with the flushes.9'10 There was evidence that this was not an effect of the secreted LH since women unable to secrete LH flushed11 and the abolition of LH pulses by means of GnRH agonist administration did not abolish flushing.12 It has been suggested that GnRH spikes are a factor in flushing13 but women with isolated gonadotrophin deficiency which is presumed to involve deficiency of GnRH secretion get flushes14 therefore GnRH action is not essential. It is reasonable to deduce that central neurotransmitter activity is affected by the fall in oestrogen levels. This will affect hypothalamic GnRH neurone activity as part of the hypothalamic-ovarian feedback mechanism and affect the activity of the adjacent neurones in the thermoregulatory centre. Alternatively changes in thermoregulatory neurones may trigger activity in GnRH neurones as a secondary effect. The mechanisms which might mediate these effects are little understood but include changes in activity of catechol oestrogens, 5-hydroxytryptamine, noradrenalin and
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endogenous opiate neurotransmitter pathways—all of which can be influenced by oestrogen. There is conflicting evidence that inhibition of opiate receptors may be associated with a reduction in flushing.1516 At the biophysical level the events surrounding the flush event have been defined in detail by a series of researchers.10>17~19 The most prominent feature of the flush is rapid vasodilation in the skin of parts of the upper body in particular17 and is accompanied by an increase in heart rate and a reduction in skin resistance.20 As a result, skin temperature rises by several degrees and core temperature falls slightly.10'21 The flush sensation tends to last a few minutes but can be more prolonged22 and the sweating sensation takes longer to clear. Peripheral vasodilation is controlled principally by sympathetic vasomotor tone. Increased tone causing vasoconstriction and decreased tone permitting increased flow. Studies of the control of vasodilation/vasoconstriction reveal a rapid continuous fluctuation in this balance. A difference in the fine tuning of control has been reported by Brincat et al.23 where alternating exposure of one hand to hot and cold stimuli evoked a parallel vasoconstriction/ vasodilation in the opposite hand to a much greater degree than in subjects who did not suffer flushes. This is termed thermal entrainment and is detectable as a functional difference at times when the women are not actually flushing. Another effect which is detectable outside of the actual flush is a difference in the response of many women who flush to a cold stimulus applied to the neck. This is the vasoconstrictor ice response which normally induces peripheral vasoconstriction. This effect is absent in women who flush and returns in ex-flushers.24 Both thermal entrainment and the vasoconstrictor ice response are known to be abnormal in Raynaud's Syndrome. Any clinician who uses HRT to help women with flushes will know that this symptom responds very well to oestrogen and often evokes patient gratitude because the benefit is usually quickly perceived. However, there is a significant placebo response when flushes are treated so studies aimed at demonstrating the efficacy of oestrogen therapy should be appropriately designed. The classic study was that of Coope et al.25 who used a double-blind placebo controlled crossover model. Whilst there was a significant improvement in the number of flushes in those who received placebo first this was less than in the other group and at the crossover the former group continued to improve when changed
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to oestrogen whereas the latter group rapidly deteriorated when changed to placebo. The other well known placebo controlled double blind study which clearly demonstrates the efficacy of oestrogen was that of Campbell and Whitehead.26 There was an improvement on placebo (mean graphic scale 10) but a significantly greater improvement on Premarin (mean graphic scale 44). In relation to vasomotor symptomatology all standard HRT formulations should prove effective, however, if a woman fails to respond to one oestrogen dose she may well respond to an increase in dose. There can be considerable variation in the absorption of oestrogen and progestogen preparations thus where the woman's current therapy has been given time to work, but the flushes are unrelieved it is sensible to try varying the dose or considering alternative HRT preparations or routes of administration.
PSYCHOLOGICAL SYMPTOMS In surveys of menopausal symptomatology many women report psychological symptoms as a problem.3'27 Understanding the relationship between minor psychological symptoms and the climacteric is frought with difficulties because of the complex nature of the factors which may affect psychological functioning.28 These include personality, cyclical hormone changes, a reduction in oestrogen levels in the perimenopause, changes in social and family stresses and status and the accumulation of minor ailments with age, as well as the oestrogen deficiency of the postmenopausal years. There will also be a small group of women with true psychiatric syndromes who just happen to be climacteric at the time. The literature on this subject is confusing and may perhaps best be summarised by stating that there is little evidence for an association between the menopause and full blown psychiatric disease, such as depression, but that 'minor' psychological upset does occur in many women during the menopausal transition, especially before the menopause is thoroughly established. The action of HRT in the alleviation of the psychiatric/psychological upset is to relieve many of these symptoms and to induce an increased sense of well-being. Where there is a full blown psychiatric syndrome the effect of HRT is less predictable but some women will be improved significantly.
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The available evidence can be divided into: 1. Evidence on the relationship between the menopause and psychiatric symptomatology. 2. Evidence on the effect of oestrogen therapy on symptoms from controlled trials. 3. Evidence for possible mechanisms for an action of oestrogen on central neurotransmitter function. Over the past 20 years several cross-sectional surveys of perimenopausal and postmenopausal symptomatology have indicated that minor psychological symptoms are commonly reported in those phases of life,2'3'6'27-29~31 however, a recent 3 year longitudinal study of 541 women approaching the menopause found that the 69 who became menopausal, and did not have HRT, showed only an increase in hot flushes and decreased introspection compared with 101 age matched controls who remained premenopausal.32 The carefully controlled community survey of Bungay et al.27 indicated that a range of minor but potentially disabling psychological symptoms became more frequent in the fifth decade with a decline in the sixth. These include poor concentration, loss of confidence, difficulty making decisions and tiredness. The classification of the women was by age rather than menopausal status so many of those who were symptomatic could have been perimenopausal. The finding that many of the minor psychological disturbances often preceed the cessation of menstruation and correlate with the phase of fluctuating hormone profiles is a feature of several other studies.30>33>34 In the investigation of the effect of HRT on psychological disorder at the menopause the necessity for placebo control and adequate psychological methodology should be obvious since these symptoms will be particularly prone to show placebo responses. This is well illustrated by the hormone implant treatment study of Montgomery et al.34 where the self-rating scales for psychological symptoms in women who were postmenopausal were improved by treatment but the improvement was no better than that induced by placebo implants. This is in contrast to the response of a perimenopausal group who did show a greater improvement on active treatment than on placebo. The placebo controlled studies vary in their design and quality but generally some improvement in minor psychological disturbance is reported.26'35"39 Where oestrogen is used in an attempt to treat severe depressive
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illness there is a variable response.39 Overall there was an improvement compared with placebo but this was principally in a subgroup of the women studied. In that group there was a clinically important improvement in their serious illness and this did not necessarily correlate with menopausal status. This may indicate a beneficial central effect of oestrogen in addition to the simple correction of oestrogen deficiency. This type of response is also reported in studies on the treatment of premenstrual syndrome where the generation of relatively high oestradiol levels induces greatly improved psychological functioning.40'41 What evidence is there to support an effect of oestradiol on central neurotransmitter function in relation to psychological functioning? Any evidence must necessarily be indirect and is limited by the lack of well proven biochemical mechanisms for depressive illness. Possible mechanisms include actions on monoamine pathways by affecting noradrenergic, dopaminergic or 5-hydroxytryptamine neurones. Aylward42 demonstrated in a placebo controlled study that oestrogen reduces plasma tryptophan levels which may affect 5-hydroxytryptamine activity. Oestrogen may also affect monoamine-oxidase inhibitor activity.43'44 We have recently studied these neuroendocrine effects in symptomatic hysterectomised women and found that the central effect of implanted oestradiol does not appear to involve 5-hydroxytryptamine uptake mechanisms45 but that it may alter noradrenergic function but not via alterations in alpha-2 adrenoreceptor sensitivity.46 Neuroendocrine studies in the human are difficult but without further study of this area our understanding of the effect of oestrogen therapy on the brain will remain scanty. The evidence presented appears to explain the firm impression of many of us who treat women with HRT that many women experience an improvement in their psychological functioning and have a greater sense of well-being whereas our psychiatric colleagues who are treating women with clinical depression remain less convinced. We appear to be treating different populations. Gath and Isles47 have highlighted this difference by using the terms 'depressive syndrome' and 'depressive mood'. The latter being the less severe condition but having an association with the menopause. This does not seek to imply that depressive mood should be ignored. It is distressing for the woman and her family and where it can be relieved by HRT the woman's life can be transformed.
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SEXUAL FUNCTION Like psychological symptom problems sexual difficulties in the perimenopausal and postmenopausal years are a complex issue affected by a wide range of social, environmental and interpersonal factors which may be independent of the menopause. These difficulties may also be affected by direct effects of oestrogen deficiency on the lower genital tract and possible effects on psychological functioning as discussed above. There is evidence that sexual activity declines with advancing age48 particularly over the years of the menopausal transition. 4950 Since sexual activity involves two partners, it is important to avoid the assumption that sexual dysfunction at the menopause is always a primary female problem. Male sexual dysfunction with decreased desire and impotence will be the primary problem for some couples and in others it will have become the major issue having resulted from a change in the sexual relationship due to female dyspareunia or altered responsiveness and sensation.51 The dyspareunia may relate to decreased lubricating secretions in the vagina with reduced blood flow to that area and decreased sensation. Once the problem becomes established a lack of confidence can easily be induced in both partners further accentuating the problem. This chapter specifically addresses the role of HRT but it would be a distortion of sensible practice to view HRT as the whole answer to sexual difficulties in menopausal women or to see oestrogen deficiency as their only source. Even if hormonal therapy is to be tried, a sensitive but detailed history of the problem should be attempted and a range of advice given. Specialised sex therapy may be required, no matter how good the response to hormones, since the problem may have set up reactions within the sexual relationship which can be difficult to undo. The relevant sex therapy techniques as practiced in Oxford are discussed in practical terms by Hawton.52 There is some evidence that sexual difficulties will respond to HRT which can increase lubrication during the sexual response53 and may increase sexual enjoyment, desire and orgasmic frequency.54 The role of androgen supplementation in women receiving HRT who have sexual dysfunction remains controversial. In a study comparing oestrogen, testosterone, both and placebo in oophorectomised women there was an improvement in depressed mood on all three hormonal preparations and on testosterone there
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was an increased level of sexual desire and fantasies.55 However, when comparing oestradiol implant therapy with oestradiol plus testosterone implants in oophorectomised women Dow et al.56 observed improved sexual functioning on both forms of therapy with no additional benefit from testosterone. Based on this information a trial of HRT in appropriate cases of menopausal sexual dysfunction supplemented by counselling is a good approach. Testosterone can be reserved for therapeutic trial in unresponsive cases. Where the sexual history reveals major problems more specialised sex therapy should be introduced at an early stage. SKIN There is evidence that the collagen component of skin undergoes a similar decline to the collagen component of bone.57'58 The collagen is a major component of the dermal layer of skin and as it decreases in thickness the skin is more easily damaged and takes on a transparent appearance.59 The use of HRT will prevent,60 or restore this loss.61 This effect of HRT on skin collagen is not correlated with duration of HRT use.62 LOWER URINARY TRACT PROBLEMS Lower urinary tract symptoms increase with advancing age and may be accentuated at the menopause.63 Cardozo64 has demonstrated that more than 50% of a menopause clinic population have some lower urinary tract symptoms, especially stress incontinence but on urodynamic investigation less than 20% had genuine stress incontinence. She could not identify any consistent 'menopause effect' on urethral function. However, it is reasonable to relate some of the observed urethral dysfunction to the menopausal decline in oestrogen status, since the urethra is oestrogen sensitive65 and oestrogen replacement improves urethral function.66'67 The oestrogen effect maybe partly mediated via changes in the collagen component of the urethral tissue. If this is lost during oestrogen deficiency, then it may affect urethral performance in maintaining an adequate closing pressure. Certainly there is evidence that skin collagen content, which declines with declining oestrogen status, does correlate with urethral function.68 Studies on the effect of oestrogen treatment on urethral closing pressure have not yielded consistently beneficial results. In stress incontinence we ideally wish to observe an improvement in
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urethral closing pressure on the application of the stress which results when intra-abdominal pressure is raised. HRT has been found to improve that parameter in some studies.66'67'69 Symptomatology can be a problem and many of a range of symptoms can be improved using HRT. 6 7 7 0 Overall a wide range of menopause related symptoms may be alleviated by means of using HRT. Many of these symptoms are subject to a significant placebo response, therefore it is essential that care is taken to assess the population addressed by the study and whether there is an adequate control group for the problem under consideration. REFERENCES 1 Barlow DH, Brockie JA, Recs CMP. Oxford General Practitioners Menopause Study Group. Study of general practice consultations and menopausal problems. Br Med J 1991; 302: 274-276 2 McKinlay SM, Jefferys M. The menopausal syndrome. Br J Prev Soc Med 1974; 28: 108-115 3 Barlow DH, Grosset KA, Hart H, Hart DM. A study of the experience of Glasgow women in the climacteric years. Br J Obstet Gynaecol 1989; 96: 11921197 4 Chakravarti S, Collins WP, Newton JR, Oram DH, Studd JW. Endocrine changes and symptomatology after oophorectomy in premenopausal women. Br J Obstet Gynaecol 1977; 84: 769-775 5 Hagstad A, Janson PO. The epidemiology of climacteric symptoms. Acta Obstet Gynecol Scand Suppl 1986; 134: 59-65 6 Gath D, Osborn M, Bungay G, lies S, Day A, Bond A, Passingham C. Psychiatric disorder and gynaecological symptoms in middle aged women: a community survey. Br Med J Clin Res 1987; 294: 213-218 7 Hutton JD, Jacobs HS, Murray MA, James VH. Relation between plasma oestrone and oestradiol and climacteric symptoms. Lancet 1978; 1: 678-681 8 Aitken JM, Davidson A, England P, Govan AD, Hart DM, Kelly A, Lindsay R, Moffatt A. The relationship between menopausal vasomotor symptoms and gonadotrophin excretion in urine after oophorectomy. J Obstet Gynaecol Br Commonw 1974; 81: 150-154 9 Casper RF, Yen SS, Wilkes MM. Menopausal flushes: a neuroendocrinc link with pulsatile luteninizing hormone secreation. Science 1979; 205: 823-825 10 Tataryn IV, Meldrum DR, Lu KH, Frumar AM, Judd HL. LH, FSH and skin temperature during the menopausal hot flash. J Clin Endocrinol Metab 1979; 49: 152-154 11 Meldrum DR, Erlik Y, Lu JK, Judd HL. Objectively recorded hot flushes in patients with pituitary insufficiency. J Clin Endocrinol Metab 1981; 52: 684-688 12 Lightman SL, Jacobs HS, Maguire AK. Down-regulation of gonadotrophin secretion in postmenopausal women by a superactive LHRH analogue: lack of effect on menopausal flushing. Br J Obstet Gynaecol 1982; 89: 977-980 13 Ravnikar V, Elkind-Hirsch K, Schiff I, Ryan KJ, Tulchinsky D. Vasomotor
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flushes and the release of peripheral immunorcactive luteinizing hormonereleasing hormone in postmenopausal women. Fertil Steril 1984; 41: 881-887 Gambone J, Meldrum DR, Laufer L, Chang RJ, Lu JK, Judd HL. Further delineation of hypothalamic dysfunction responsible for mcnopausal hot flashes. J Clin Endocrinol Metab 1984; 59: 1097-1102 Lightman SL, Jacobs HS. Naloxone: non-steroidal treatment for postmenopausal flushing? [letter]. Lancet 1979; ii: 1071 DeFazio J, Verheugen C, Chetkowski R, Nass T, Judd HL, Meldrum DR. The effects of naloxone on hot flashes and gonadotropin secretion in postmenopausal women. J Clin Endocrinol Metab 1984; 58: 578-581 Sturdee DW, Reece BL. Thermography of menopausal hot flushes. Maturitas 1979; 1: 201-205 Nesheim BI, Saetre T. Changes in skin blood flow and body temperatures during climacteric hot flushes. Maturitas 1982; 4: 49-55 Tataryn IV, Lomax P, Bajorek JG, Chesarck W, Meldrum DR, Judd HL. Postmenopausal hot flushes: a disorder of thermoregulation. Maturitas 1980; 2: 101-107 Silverman RW, Bajorek JG, Lomax P, Tataryn IV. Monitoring the pathophysiological correlates of post-menopausal hot flushes. Maturitas 1981; 3: 39—46 Kronenberg F, Cote LJ, Linkie DM, Dyrenfurth I, Downey JA. Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes. Maturitas 1984; 6: 31-43 Sturdee DW, Wilson KA, Pipili E, Crocker AD. Physiological aspects of menopausal hot flush. Br Med J 1978; 2: 79-80 Brincat M, de-Trafford JC, Lafferty K, Studd JW. Peripheral vasomotor control and menopausal flushing—a preliminary report. Br J Obstet Gynaecol 1984; 91: 1107-1110 Rees MC, Barlow DH. Absence of sustained reflex vasoconstriction in women with menopausal flushes. Hum Reprod 1988; 3: 823-825 Coope J, Thomson JM, Poller L. Effects of 'natural oestrogen' replacement therapy on menopausal symptoms and blood clotting. Br Med J 1975; 4: 139-143 Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaecol 1977; 4: 31-47 Bungay GT, Vessey MP, McPherson CK. Study of symptoms in middle-life with special reference to the menopause. Br Med J 1980; 281: 181-183 Schneider M, Brotherton P. Physiological, psychological and situational stresses in depression during the climacteric. Maturitas 1979; 1: 153—158 Jaszmann L. Epidemiology of climacteric and post-climacteric complaints. In: van Keep PA, Lauritzen C, eds. Ageing and Oestrogens. Karger, Basel. 1973: pp. 22-34 Ballinger CB. Psychiatric morbidity and the menopause; screening of general population sample. Br Med J 1975; 3: 344-346 Hunter MS. Somatic experience of the menopause: a prospective study. Psychosom Med 1990; 52: 357-367 Matthews KA, Wing RR, Kuller LH et al. Influences of natural menopause on psychological characteristics and symptoms of middle-aged healthy women. J Consult Clin Psychol 1990; 58: 345-351 Weissman MM. The myth of involutional melancholia. J Am Med Assoc 1979; 242: 742-744 Montgomery JC, Appleby L, Brincat M et al. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet 1987; i: 297-299 Martin PL, Burnier AM, Segre EJ, Huix FJ. Graded sequential therapy in the menopause: a double-blind study. Am J Obstet Gynecol 1971; 111: 178-186
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36 Dennerstein L, Burrows GD, Hyman GJ, Sharpe K. Hormone therapy and affect. Maruritas 1979; 1: 247-259 37 Dennerstein L, Burrows GD, Wood C, Hyman G. Hormones and sexuality: effect of estrogen and progestogen. Obstet Gynecol 1980; 56: 316-322 38 Paterson ME. A randomised, double-blind, cross-over study into the effect of sequential mestranol and norethisterone on climacteric symptoms and biochemical parameters. Maruritas 1982; 4: 83-94 39 Klaiber EL, Broverman DM, Vogel W, Kobayashi Y. Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 1979; 36: 550-554 40 Magos AL, Brincat M, Studd JW. Treatment of the premenstrual syndrome by subcutaneous estradiol implants and cyclical oral norethisterone: placebo controlled study. Br Med J Clin Res 1986; 292: 1629-1633 41 Watson NR, Studd JW, Riddle AF, Sawas M. Suppression of ovulation by transdermal oestradiol patches. BMJ 1988; 297: 900-901 42 Aylward M. Estrogens, plasma tryptophan levels in perimenopausal patients. In: Campbell S, ed. The Management of the Menopause and Postmenopausal Years. Lancaster: MTP, 1976: pp. 135-147 43 Klaiber EL, Broverman DM, Vogel W, Kobayashi Y, Moriarty D. Effects of estrogen therapy on plasma MAO activity and EEG driving responses of depressed women. Am J Psychiatry 1972; 128: 1492-1498 44 Luhby AL, Davis P, Murphy M, Gordon M, Brin M, Spiegel H. Pyridoxine and oral contraceptives. Lancet 1970; ii: 1083 45 Best NR, Barlow DH, Rees MP, Cowen PJ. Lack of effects of oestradiol implant on platelet imipramine and 5-HT2 receptor binding in menopausal subjects. Psychopharmacology (Berlin) 1989; 98: 561 46 Best NR, Rees MP, Barlow DH, Cowan PJ. Effect of oestradiol implant onnoradrcnergic function and mood in climacteric subjects. Sixth International Congress on the Menopause 1990; abs 266: (Abstract) 47 Gath D, Isles S. Psychological effects of the menopause. In: Drife JO, Studd JWW, eds. HRT and Osteoporosis. London: Springer, 1990: pp. 35-42 48 Pfeiffer E, Verwoerdt A, Davis GO Sexual behavior in middle life. Am J Psychiatry 1972; 128: 1262-1267 49 Keep PA, KeUcrhals JM. The impact of socio-cultural factors on symptom formation. Some results of a study on ageing women in Switzerland. Psychother Psychosom 1974; 23: 251-263 50 Sarrel PM, Whitehead MI. Sex and menopause: defining the issues. Maruritas 1985; 7: 217-224 51 Sarrel PM. Sex problems after menopause: a study of fifty married couples treated in a sex counselling programme. Maruritas 1982; 4: 231-237 52 Hawton K. Sex Therapy: A Practical Guide. Oxford: Oxford University Press, 1985. 53 Semmens JP, Wagner G. Estrogen deprivation and vaginal function in postmenopausal women. J Am Med Assoc 1982; 248: 445-448 54 Dennerstein L, Wood C, Burrows GD. Sexual response following hysterectomy and oophorecomy. Obstet Gynecol 1977; 49: 92-96 55 Sherwin BB, Gelfand MM. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 1985; 151: 153-160 56 Dow MG, Hart DM, Forrest CA. Hormonal treatments of sexual unresponsivcness in postmenopausal women: a comparative study. Br J Obstet Gynaccol 1983; 90: 361-366 57 Brincat M, Moniz CF, Studd JW, Darby AJ, Magos A, Cooper D. Sex hormones and skin collagen content in postmenopausal women. Br Med J Clin Res 1983; 287: 1337-1338 58 Brincat M, Kabalan S, Studd JW, Moniz CF, de Trafford J, Montgomery J. A
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study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman. Obstet Gynecol 1987; 70: 840-845 McConkey B, Fraser GM, Bligb AS, Whitely H. Transparent skin and osteoporosis. Lancet 1963; i: 693-695 Brincat M, Moniz CF, Kabalan S et al. Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement. Br J Obstet Gynaecol 1987; 94: 126-129 Brincat M, Versi E, Moniz CF, Magos A, de-Trafford J, Studd JW. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol 1987; 70: 123-127 Brincat M, Moniz CJ, Studd JW et al. Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol 1985; 92: 256-259 Iosif CS, Bckassy Z. Prevalence of genito-urinary symptoms in the late menopause. Acta Obstet Gynecol Scand 1984; 63: 257-260 Cardozo L. Oestrogen deficiency and the bladder. In: Drife JO, Studd JWW, eds. HRT and Osteoporosis. London: Springer-Verlag, 1990: pp. 57-68 Packham DA. The epithelial lining of the female trigonc and urethra. Br J Urol 1971; 43: 201-205 Rud T. The effects of estrogens and gestagens on the urethral pressure profile in urinary continent and stress incontinent women. Acta Obstet Gynecol Scand 1980; 59: 265-270 Hilton P, Stanton SL. The use of intravaginal oestrogen cream in genuine stress incontinence. Br J Obstet Gynaecol 1983; 90: 940-944 Versi E, Cardozo L, Brincat M, Cooper D, Montgomery J, Studd J. Correlation of urethral physiology and skin collagen in postmenopausal women. Br J Obstet Gynaecol 1988; 95: 147-52 Bhatia NN, Bergman A, Karram MM. Effects of estrogen on urethral function in women with urinary incontinence. Am J Obstet Gynecol 1989; 160: 176-181 Wilson PD, Faragher B, Butler B, Bu'Lock D, Robinson EL, Brown AD. Treatment with oral piperazine oestrone sulphate for genuine stress incontinence in postmenopausal women. Br J Obstet Gynaecol 1987; 94: 568-574
Hormone replacement therapy and other menopause associated conditions D H Barlow Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Maternity Hospital, Oxford, UK
In Britain a large majority of the women who use Hormone Replacement Therapy (HRT) use it in order to alleviate symptoms thought to relate to the menopause. These include vasomotor instability, 'minor' psychological disturbance and sexual difficulties. Other HRT effects gained by the women include effects on maintainence of collagen, as in the skin, and on oestrogen sensitive tissues related to the lower urinary tract.
This volume devotes considerable space to the effect of hormone replacement therapy (HRT) on the potential prevention of some major health problems of older women, namely osteoporosis and its consequences, coronary artery disease and stroke. This is a correct emphasis since the potential health benefit for the population is considerable. However as a specialist working in the menopause field I have the strong impression that a large majority of HRT prescribing is aimed at the alleviation of menopause related symptomatology. In a recent survey of menopause related consultations in Oxford General Practice we found that a very large majority related to symptomatic complaints.1 HRT AND VASOMOTOR SYMPTOMATOLOGY Hot flushes and sweats are the commonest menopausal symptom complex2'3 and are particularly common where oestrogen withdrawal has been acute as at the surgical menopause.4
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Women know that the menopause brings flushes and generally cope if they are not too frequent. Unfortunately for some women the frequency is so high that life can be dominated by them. If the problem was always of short duration, again it might be easier to cope but 10% may still be having flushes into their sixties.5 Flushing and sweating attacks are clearly a menopausal problem and were shown to peak significantly during the climacteric years.6 They appear to correlate with the decline in oestrogen and eventually stabilise in the years of hypo-oestrogenism. Women who are experiencing intermittent oestrogenisation in the perimenopause may experience flushing despite being reasonably oestrogenised much of the time. Women treated with oestradiol implants may report flushes during the phase of relative oestrogen decline when an implant is clinically 'wearing off' despite circulating oestradiol levels comfortably in the premenopausal range. Despite these correlates with declining oestrogen studies comparing circulating oestrogen levels in those who flush and asymptomatic women do not discover a significant correlation between flushing and the oestrogen level.7 There have been apparent correlations between endocrine parameters and flushes but so far they have not provided us with a good understanding of the mechanism underlying this common symptom. An early idea was that gonadotrophin levels might correlate with flushing8 but this was not confirmed. Study of the acute flush episode with frequent blood sampling then revealed pulses of luteinising hormone (LH) coincident with the flushes.9'10 There was evidence that this was not an effect of the secreted LH since women unable to secrete LH flushed11 and the abolition of LH pulses by means of GnRH agonist administration did not abolish flushing.12 It has been suggested that GnRH spikes are a factor in flushing13 but women with isolated gonadotrophin deficiency which is presumed to involve deficiency of GnRH secretion get flushes14 therefore GnRH action is not essential. It is reasonable to deduce that central neurotransmitter activity is affected by the fall in oestrogen levels. This will affect hypothalamic GnRH neurone activity as part of the hypothalamic-ovarian feedback mechanism and affect the activity of the adjacent neurones in the thermoregulatory centre. Alternatively changes in thermoregulatory neurones may trigger activity in GnRH neurones as a secondary effect. The mechanisms which might mediate these effects are little understood but include changes in activity of catechol oestrogens, 5-hydroxytryptamine, noradrenalin and
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endogenous opiate neurotransmitter pathways—all of which can be influenced by oestrogen. There is conflicting evidence that inhibition of opiate receptors may be associated with a reduction in flushing.1516 At the biophysical level the events surrounding the flush event have been defined in detail by a series of researchers.10>17~19 The most prominent feature of the flush is rapid vasodilation in the skin of parts of the upper body in particular17 and is accompanied by an increase in heart rate and a reduction in skin resistance.20 As a result, skin temperature rises by several degrees and core temperature falls slightly.10'21 The flush sensation tends to last a few minutes but can be more prolonged22 and the sweating sensation takes longer to clear. Peripheral vasodilation is controlled principally by sympathetic vasomotor tone. Increased tone causing vasoconstriction and decreased tone permitting increased flow. Studies of the control of vasodilation/vasoconstriction reveal a rapid continuous fluctuation in this balance. A difference in the fine tuning of control has been reported by Brincat et al.23 where alternating exposure of one hand to hot and cold stimuli evoked a parallel vasoconstriction/ vasodilation in the opposite hand to a much greater degree than in subjects who did not suffer flushes. This is termed thermal entrainment and is detectable as a functional difference at times when the women are not actually flushing. Another effect which is detectable outside of the actual flush is a difference in the response of many women who flush to a cold stimulus applied to the neck. This is the vasoconstrictor ice response which normally induces peripheral vasoconstriction. This effect is absent in women who flush and returns in ex-flushers.24 Both thermal entrainment and the vasoconstrictor ice response are known to be abnormal in Raynaud's Syndrome. Any clinician who uses HRT to help women with flushes will know that this symptom responds very well to oestrogen and often evokes patient gratitude because the benefit is usually quickly perceived. However, there is a significant placebo response when flushes are treated so studies aimed at demonstrating the efficacy of oestrogen therapy should be appropriately designed. The classic study was that of Coope et al.25 who used a double-blind placebo controlled crossover model. Whilst there was a significant improvement in the number of flushes in those who received placebo first this was less than in the other group and at the crossover the former group continued to improve when changed
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to oestrogen whereas the latter group rapidly deteriorated when changed to placebo. The other well known placebo controlled double blind study which clearly demonstrates the efficacy of oestrogen was that of Campbell and Whitehead.26 There was an improvement on placebo (mean graphic scale 10) but a significantly greater improvement on Premarin (mean graphic scale 44). In relation to vasomotor symptomatology all standard HRT formulations should prove effective, however, if a woman fails to respond to one oestrogen dose she may well respond to an increase in dose. There can be considerable variation in the absorption of oestrogen and progestogen preparations thus where the woman's current therapy has been given time to work, but the flushes are unrelieved it is sensible to try varying the dose or considering alternative HRT preparations or routes of administration.
PSYCHOLOGICAL SYMPTOMS In surveys of menopausal symptomatology many women report psychological symptoms as a problem.3'27 Understanding the relationship between minor psychological symptoms and the climacteric is frought with difficulties because of the complex nature of the factors which may affect psychological functioning.28 These include personality, cyclical hormone changes, a reduction in oestrogen levels in the perimenopause, changes in social and family stresses and status and the accumulation of minor ailments with age, as well as the oestrogen deficiency of the postmenopausal years. There will also be a small group of women with true psychiatric syndromes who just happen to be climacteric at the time. The literature on this subject is confusing and may perhaps best be summarised by stating that there is little evidence for an association between the menopause and full blown psychiatric disease, such as depression, but that 'minor' psychological upset does occur in many women during the menopausal transition, especially before the menopause is thoroughly established. The action of HRT in the alleviation of the psychiatric/psychological upset is to relieve many of these symptoms and to induce an increased sense of well-being. Where there is a full blown psychiatric syndrome the effect of HRT is less predictable but some women will be improved significantly.
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The available evidence can be divided into: 1. Evidence on the relationship between the menopause and psychiatric symptomatology. 2. Evidence on the effect of oestrogen therapy on symptoms from controlled trials. 3. Evidence for possible mechanisms for an action of oestrogen on central neurotransmitter function. Over the past 20 years several cross-sectional surveys of perimenopausal and postmenopausal symptomatology have indicated that minor psychological symptoms are commonly reported in those phases of life,2'3'6'27-29~31 however, a recent 3 year longitudinal study of 541 women approaching the menopause found that the 69 who became menopausal, and did not have HRT, showed only an increase in hot flushes and decreased introspection compared with 101 age matched controls who remained premenopausal.32 The carefully controlled community survey of Bungay et al.27 indicated that a range of minor but potentially disabling psychological symptoms became more frequent in the fifth decade with a decline in the sixth. These include poor concentration, loss of confidence, difficulty making decisions and tiredness. The classification of the women was by age rather than menopausal status so many of those who were symptomatic could have been perimenopausal. The finding that many of the minor psychological disturbances often preceed the cessation of menstruation and correlate with the phase of fluctuating hormone profiles is a feature of several other studies.30>33>34 In the investigation of the effect of HRT on psychological disorder at the menopause the necessity for placebo control and adequate psychological methodology should be obvious since these symptoms will be particularly prone to show placebo responses. This is well illustrated by the hormone implant treatment study of Montgomery et al.34 where the self-rating scales for psychological symptoms in women who were postmenopausal were improved by treatment but the improvement was no better than that induced by placebo implants. This is in contrast to the response of a perimenopausal group who did show a greater improvement on active treatment than on placebo. The placebo controlled studies vary in their design and quality but generally some improvement in minor psychological disturbance is reported.26'35"39 Where oestrogen is used in an attempt to treat severe depressive
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illness there is a variable response.39 Overall there was an improvement compared with placebo but this was principally in a subgroup of the women studied. In that group there was a clinically important improvement in their serious illness and this did not necessarily correlate with menopausal status. This may indicate a beneficial central effect of oestrogen in addition to the simple correction of oestrogen deficiency. This type of response is also reported in studies on the treatment of premenstrual syndrome where the generation of relatively high oestradiol levels induces greatly improved psychological functioning.40'41 What evidence is there to support an effect of oestradiol on central neurotransmitter function in relation to psychological functioning? Any evidence must necessarily be indirect and is limited by the lack of well proven biochemical mechanisms for depressive illness. Possible mechanisms include actions on monoamine pathways by affecting noradrenergic, dopaminergic or 5-hydroxytryptamine neurones. Aylward42 demonstrated in a placebo controlled study that oestrogen reduces plasma tryptophan levels which may affect 5-hydroxytryptamine activity. Oestrogen may also affect monoamine-oxidase inhibitor activity.43'44 We have recently studied these neuroendocrine effects in symptomatic hysterectomised women and found that the central effect of implanted oestradiol does not appear to involve 5-hydroxytryptamine uptake mechanisms45 but that it may alter noradrenergic function but not via alterations in alpha-2 adrenoreceptor sensitivity.46 Neuroendocrine studies in the human are difficult but without further study of this area our understanding of the effect of oestrogen therapy on the brain will remain scanty. The evidence presented appears to explain the firm impression of many of us who treat women with HRT that many women experience an improvement in their psychological functioning and have a greater sense of well-being whereas our psychiatric colleagues who are treating women with clinical depression remain less convinced. We appear to be treating different populations. Gath and Isles47 have highlighted this difference by using the terms 'depressive syndrome' and 'depressive mood'. The latter being the less severe condition but having an association with the menopause. This does not seek to imply that depressive mood should be ignored. It is distressing for the woman and her family and where it can be relieved by HRT the woman's life can be transformed.
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SEXUAL FUNCTION Like psychological symptom problems sexual difficulties in the perimenopausal and postmenopausal years are a complex issue affected by a wide range of social, environmental and interpersonal factors which may be independent of the menopause. These difficulties may also be affected by direct effects of oestrogen deficiency on the lower genital tract and possible effects on psychological functioning as discussed above. There is evidence that sexual activity declines with advancing age48 particularly over the years of the menopausal transition. 4950 Since sexual activity involves two partners, it is important to avoid the assumption that sexual dysfunction at the menopause is always a primary female problem. Male sexual dysfunction with decreased desire and impotence will be the primary problem for some couples and in others it will have become the major issue having resulted from a change in the sexual relationship due to female dyspareunia or altered responsiveness and sensation.51 The dyspareunia may relate to decreased lubricating secretions in the vagina with reduced blood flow to that area and decreased sensation. Once the problem becomes established a lack of confidence can easily be induced in both partners further accentuating the problem. This chapter specifically addresses the role of HRT but it would be a distortion of sensible practice to view HRT as the whole answer to sexual difficulties in menopausal women or to see oestrogen deficiency as their only source. Even if hormonal therapy is to be tried, a sensitive but detailed history of the problem should be attempted and a range of advice given. Specialised sex therapy may be required, no matter how good the response to hormones, since the problem may have set up reactions within the sexual relationship which can be difficult to undo. The relevant sex therapy techniques as practiced in Oxford are discussed in practical terms by Hawton.52 There is some evidence that sexual difficulties will respond to HRT which can increase lubrication during the sexual response53 and may increase sexual enjoyment, desire and orgasmic frequency.54 The role of androgen supplementation in women receiving HRT who have sexual dysfunction remains controversial. In a study comparing oestrogen, testosterone, both and placebo in oophorectomised women there was an improvement in depressed mood on all three hormonal preparations and on testosterone there
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was an increased level of sexual desire and fantasies.55 However, when comparing oestradiol implant therapy with oestradiol plus testosterone implants in oophorectomised women Dow et al.56 observed improved sexual functioning on both forms of therapy with no additional benefit from testosterone. Based on this information a trial of HRT in appropriate cases of menopausal sexual dysfunction supplemented by counselling is a good approach. Testosterone can be reserved for therapeutic trial in unresponsive cases. Where the sexual history reveals major problems more specialised sex therapy should be introduced at an early stage. SKIN There is evidence that the collagen component of skin undergoes a similar decline to the collagen component of bone.57'58 The collagen is a major component of the dermal layer of skin and as it decreases in thickness the skin is more easily damaged and takes on a transparent appearance.59 The use of HRT will prevent,60 or restore this loss.61 This effect of HRT on skin collagen is not correlated with duration of HRT use.62 LOWER URINARY TRACT PROBLEMS Lower urinary tract symptoms increase with advancing age and may be accentuated at the menopause.63 Cardozo64 has demonstrated that more than 50% of a menopause clinic population have some lower urinary tract symptoms, especially stress incontinence but on urodynamic investigation less than 20% had genuine stress incontinence. She could not identify any consistent 'menopause effect' on urethral function. However, it is reasonable to relate some of the observed urethral dysfunction to the menopausal decline in oestrogen status, since the urethra is oestrogen sensitive65 and oestrogen replacement improves urethral function.66'67 The oestrogen effect maybe partly mediated via changes in the collagen component of the urethral tissue. If this is lost during oestrogen deficiency, then it may affect urethral performance in maintaining an adequate closing pressure. Certainly there is evidence that skin collagen content, which declines with declining oestrogen status, does correlate with urethral function.68 Studies on the effect of oestrogen treatment on urethral closing pressure have not yielded consistently beneficial results. In stress incontinence we ideally wish to observe an improvement in
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urethral closing pressure on the application of the stress which results when intra-abdominal pressure is raised. HRT has been found to improve that parameter in some studies.66'67'69 Symptomatology can be a problem and many of a range of symptoms can be improved using HRT. 6 7 7 0 Overall a wide range of menopause related symptoms may be alleviated by means of using HRT. Many of these symptoms are subject to a significant placebo response, therefore it is essential that care is taken to assess the population addressed by the study and whether there is an adequate control group for the problem under consideration. REFERENCES 1 Barlow DH, Brockie JA, Recs CMP. Oxford General Practitioners Menopause Study Group. Study of general practice consultations and menopausal problems. Br Med J 1991; 302: 274-276 2 McKinlay SM, Jefferys M. The menopausal syndrome. Br J Prev Soc Med 1974; 28: 108-115 3 Barlow DH, Grosset KA, Hart H, Hart DM. A study of the experience of Glasgow women in the climacteric years. Br J Obstet Gynaecol 1989; 96: 11921197 4 Chakravarti S, Collins WP, Newton JR, Oram DH, Studd JW. Endocrine changes and symptomatology after oophorectomy in premenopausal women. Br J Obstet Gynaecol 1977; 84: 769-775 5 Hagstad A, Janson PO. The epidemiology of climacteric symptoms. Acta Obstet Gynecol Scand Suppl 1986; 134: 59-65 6 Gath D, Osborn M, Bungay G, lies S, Day A, Bond A, Passingham C. Psychiatric disorder and gynaecological symptoms in middle aged women: a community survey. Br Med J Clin Res 1987; 294: 213-218 7 Hutton JD, Jacobs HS, Murray MA, James VH. Relation between plasma oestrone and oestradiol and climacteric symptoms. Lancet 1978; 1: 678-681 8 Aitken JM, Davidson A, England P, Govan AD, Hart DM, Kelly A, Lindsay R, Moffatt A. The relationship between menopausal vasomotor symptoms and gonadotrophin excretion in urine after oophorectomy. J Obstet Gynaecol Br Commonw 1974; 81: 150-154 9 Casper RF, Yen SS, Wilkes MM. Menopausal flushes: a neuroendocrinc link with pulsatile luteninizing hormone secreation. Science 1979; 205: 823-825 10 Tataryn IV, Meldrum DR, Lu KH, Frumar AM, Judd HL. LH, FSH and skin temperature during the menopausal hot flash. J Clin Endocrinol Metab 1979; 49: 152-154 11 Meldrum DR, Erlik Y, Lu JK, Judd HL. Objectively recorded hot flushes in patients with pituitary insufficiency. J Clin Endocrinol Metab 1981; 52: 684-688 12 Lightman SL, Jacobs HS, Maguire AK. Down-regulation of gonadotrophin secretion in postmenopausal women by a superactive LHRH analogue: lack of effect on menopausal flushing. Br J Obstet Gynaecol 1982; 89: 977-980 13 Ravnikar V, Elkind-Hirsch K, Schiff I, Ryan KJ, Tulchinsky D. Vasomotor
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study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman. Obstet Gynecol 1987; 70: 840-845 McConkey B, Fraser GM, Bligb AS, Whitely H. Transparent skin and osteoporosis. Lancet 1963; i: 693-695 Brincat M, Moniz CF, Kabalan S et al. Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement. Br J Obstet Gynaecol 1987; 94: 126-129 Brincat M, Versi E, Moniz CF, Magos A, de-Trafford J, Studd JW. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol 1987; 70: 123-127 Brincat M, Moniz CJ, Studd JW et al. Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol 1985; 92: 256-259 Iosif CS, Bckassy Z. Prevalence of genito-urinary symptoms in the late menopause. Acta Obstet Gynecol Scand 1984; 63: 257-260 Cardozo L. Oestrogen deficiency and the bladder. In: Drife JO, Studd JWW, eds. HRT and Osteoporosis. London: Springer-Verlag, 1990: pp. 57-68 Packham DA. The epithelial lining of the female trigonc and urethra. Br J Urol 1971; 43: 201-205 Rud T. The effects of estrogens and gestagens on the urethral pressure profile in urinary continent and stress incontinent women. Acta Obstet Gynecol Scand 1980; 59: 265-270 Hilton P, Stanton SL. The use of intravaginal oestrogen cream in genuine stress incontinence. Br J Obstet Gynaecol 1983; 90: 940-944 Versi E, Cardozo L, Brincat M, Cooper D, Montgomery J, Studd J. Correlation of urethral physiology and skin collagen in postmenopausal women. Br J Obstet Gynaecol 1988; 95: 147-52 Bhatia NN, Bergman A, Karram MM. Effects of estrogen on urethral function in women with urinary incontinence. Am J Obstet Gynecol 1989; 160: 176-181 Wilson PD, Faragher B, Butler B, Bu'Lock D, Robinson EL, Brown AD. Treatment with oral piperazine oestrone sulphate for genuine stress incontinence in postmenopausal women. Br J Obstet Gynaecol 1987; 94: 568-574
