Current preparations of HRT: advantages and disadvantages

Current Obstetrics & Gynaecology (1997) 7, 197-203 © 1997 Harcourt Brace & Co. Ltd

Mini-symposium: Menopause

Current preparations of HRT: advantages and disadvantages

M. Brincat, R. Galea and Y. Muscat Baron many sex-related problems, but apart from one study3 this has never been substantiated. Sedatives and tranquillizers have been widely prescribed for over a century along with barbiturates, diazepam and similar drugs. Such therapy only adds to the lethargy and general loss of interest in life and certainly does nothing to prevent symptoms like flushing, although, surprisingly, they have been prescribed for this symptom as well. It is a sad fact of contemporary life that about 40% of middle-aged and elderly women have had long courses of psychoactive drugs. Amongst the adrenergic agents currently used clonidine, an adrenergic agonist, seems to have some potential. Clayden et aP supervised a multi-centre, placebo-controlled, crossover study on 100 women and reported significant benefit in controlling the severity and duration of flushes with minimal sideeffects. Lindsay and HaW failed, however, to find any difference in flushing episodes when clonidine was compared to placebo. Propranolol has been tried with conflicting results. Alcoff et al 6obtained a difference in flushing episodes when compared to placebo. Methyldopa7 and naproxen* have also been suggested, but once more results, with regard to their use in the relief of flushes, are conflicting.

INTRODUCTION Women now spend 30% of their lives after the menopause in a state of profound sex-steroid deprivation. The realization of the profound changes that occur as a result of this ovarian failure, and the relatively simple treatments that are available for the condition, make it imperative that more effort should be dedicated to the study of the postmenopausal years with specialist clinics being more widely available to women. The treatment of choice for the management of menopausal symptoms and sequelae is oestrogen therapy, which should, in most cases, successfully correct this deficiency state. This hypoestrogenaemic state leads to multisystem disorders. Other treatments available only serve, at best, to manage a particular symptom without the multisystemic effect of oestrogens. In some cases serious side-effects occur that could be worse than any possible from properly managed hormone replacement.

NON-HORMONAL TREATMENT Geist and Mintz' proposed irradiating the pituitary so as to suppress excess production of gonadotrophins, which they believed caused flushing. Their results were not encouraging. More recently, suppression of pituitary activity using GnRH analogues has proved not only to be useless in suppressing flushes, but also actually to provoke such flushes.' Vitamin E has been proposed for the treatment and the prevention of

HORMONAL The commonly used oestrogen and progestin hormone replacement therapies are listed in the table.

Progestogens

51. Brincat PhD(Lond), MRCOG, R. Galea, 'l: Muscat-Baron, Department of Obstetrics and Gynaecology, St Luke's Hospital, Malta Correspondence to: M B

Although the menopause can also be described as a progesterone-deficiency state, in addition to it being

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Current Obstetrics & Gynaecology Table Commonly used oestrogen and progestia hormone replacement Iherapy

Oestrogen Oratpreparations Oestradiol valerate

Conjugated equine oestrogens Ethinyl oestradiol Piperazine oestronesulphate Mi~ronized 1713oestradiol Mestranol Parenterrdpreparations Transdermal oestradiol patches Vaginal conjugatedoestrogen Vaginal 17[3oeslradiol Oeslradiol pellets Oestradiol hemihydrate(ring)

1-2 mg 0.625-1.25 mg

5-I0 lag 1.0 mg 0.5-2.0 mg 0.05--O.1mg twiceweekly 0.2-0.625 mg 2 ~o7 times ueekly 1.0 mg l to 3 timesweekly 25, 50, 100 mg exery 6 months 7.5 lag

Progestins 2.5-50 mg daily or 10 mg 12 to 14 days per month 20-40 mg Megestrol acetate 5 mg Norethisterone 1.25-5 mg Norethisteroneacetate 0.15 mg Norgestrel kevonorgestrel 25-75 lag 10rag Dydrogesterone 100-300 mg Micronized progesterone Injectablehydroxyprogesteronecaproate 125 mffml Medroxyprogesterone acetate

an oestrogen-deficiency state, the role o f progestogens on their own as treatment for menopausal symptoms has still not been clearly defined. Both norethisterone 9 and medroxyprogesterone have been reported as useful 'D suppressing flt~shes and have been shown to be useful in the prevention o f postmenopausal bone toss, The gestagens used in these studies were medroxyprogesterone, megestrol and norethisterone. ~uz Oral progesterone is available in a micronized form, but has not gained widespread use at present. Natural oral micronized progesterone was used in one study to assess its antihyperten~ive properties in hypertensive women. This was found to be effective in reducing b~ood pressure in these women and did so in a doserelated fashion, i.e. the higher the dose of progesterone, the greater the drop in blood pressure. Blood pressure, however, tended to drop to a c o m m o n mean regardless of dose, which indicated that natural progesterone was acting in a manner similar to calcium antagonists popular at the time. '3 The dose range used was between 200 and 800 mg daily. Progesterone can also be applied as a cream or as a vaginal pessary. Despite the current media interest in Yam-derived natural progesterone there is a scarcity o f scientific evidence, and the low serum levels achieved by application o f such creams are not, as yet, known to have any systemic effects other than, possibly, some relief from hot flushes. Systemic gestagens delivered in patches as part o f sequential HRT have been pioneered in the last few years and are effective in achieving cycle control and in preventing endometrial and cystic hyperplasia."

Anabotic steroids In women, androgens have been used in the prevention and treatment of postmenopausal osteoporosis. Stanozolol, an anabolic steroid, has been studied extensively and shown to increase total body calcium in patients with established osteoporosis? ~ Its use in the prevention o f postmenopausal bone loss, however, remains to be determined. Oestrogens Oestrogen-replacement therapy is the appropriate overa[| treatment for problems caused by ovarian failure. The aim of a therapeutic regimen is to provide the most effective treatment with the least side-effects. Oestrogens may be given either orally or parenterally, i.e. percutaneously, transvaginally, cream or skin patches. Oestrogens can also be given subcutaneously as implants. The pharmacodynamies and biochemical effects o f exogenous oestrogens can vary markedly with the route o f administration. Oral oestrogens The oral route is the most popular. Its major difference from the parenteral route is that administered oestrogens are exposed to the gastrointestinal tract, the portal venous syztem and the liver. Oestradiol is preferentially converted to oestrone in the gastrointestinal tract." The portal venous system rapidly transfers the absorbed steroid, almost in the form o f a

Current preparations of HRT 'bolus', into hepatic tissue where much of the administered oestrogen is metabolized and inactivated before the systemic circulation is reached. This is known as the 'first-pass" effect. Glucuronidation of oestrogen occurs almost exclusively in the liver, so percutaneous and subcutaneous oestradiol administration are not associated with an increase in plasma oestrone-3-glucuronide levels? 7 As a result of the first-pass effect, oral oestrogens have to be given at a higher dose than parenteral therapy in order to maintain the relief of symptoms. The induction of liver enzymes, particularly the glucoronidase enzymes, by other drugs such as antiepileptics may result in such a rapid oestrogen inactivation that the administered steroid is not clinically effective. Also, oral oestrogens may influence the production of renin substrate, antithrombin III, and high and low density lipoproteins. Oral oestrogens are more potent than parenterallyadministered oestrogens in elevating HDL-cholesterol, 's thereby increasing the HDL/LDL ratio with the consequent beneficial implications for arterial disease. '9 By depressing antithrombin III activity, oral oestrogens might be contraindicated in women with a history of clotting disorder, 2° and likewise in hypertensives because of the theoretical risk of alteration in renin substrate. It must be emphasized, however, that these last two contraindications and other theoretical ones, generally refer to synthetic oral oestrogens and, therefore, should not be extrapolated for the natural oral oestrogens that are used in hormone replacement. Synthetic oestrogens should be avoided in postmenopausal women unless given in small doses. Parenteral oestrogens Parenteral oestrogens are particularly advantageous when oral therapy causes epigastric discomfort and flatulence, and when patients have a psychological aversion to taking tablets. They have all the beneficial effects of oral oestrogens. Vaghtal oeslrogen creams These have long been used in the treatment of atrophic vaginitis, on the assumption that they produced a local effect only. Whitehead et al,2t however, showed that the plasma levels of oestrone and oestradiol achieved using a standard regimen daily dose of 1.25 mg of conjugated oestrogen cream are the same or higher than those produced by the same dose of oral conjugated oestrogens. Very low daily doses of vaginal oestrogens (0.1 mg) are capable of producing significant changes in vaginal cytology and do not cause a rise in plasma oestrogens. At this low serum level, however, there is no relief of the generalized symptoms of the climacteric, and there are, as yet, no long-term studies indicating

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that even this low dosage does not cause deleterious effects on the endometrium when given continuously over a long period. The rate of absorption of oestrogens from the vagina depends on the state of the vagina. As vascularity decreases, so does absorption. The rate of absorption also depends on the medium in which the oestradiol is suspended?2 Percutaneous oestrogen cretans This mode of delivery is becoming increasingly popular. A preparation that involves the daily application of oestradiol gel on the skin (Besins) is available. The standard manufacturer's recommended dose is 5g cream containing 3 mg of ocstradiol daily. The method of administration gives a physiological serum oestradiol to oestrone ratio by bypassing the enterohepatic circulation. The avoidance of the first-pass liver effect is common to both percutaneous and subcutaneous therapy. Various studies have shown that this method gives good relief of symptoms and is safe in postmenopausal women, in whom it has also been shown to increase skin collagen content at the same dosage.23 The daily application of cream (gel) requires patient compliance, since some women find it sticky. The gel dries up quickly, however, and our own experience has not shown any real problems. Percutaneous cream leads to a relatively higher increase in serum oestradiol and achieves serum levels that are maintained for longer when compared to oral preparations?4

Percutaneous oeslrogen patches The transdermal patch can administer oestradiol at controlled rates of 0.25, 0.5, and 0.1 mg/day, depending on the surface area of the patch. Steady concentrations can be obtained if the systems are worn for 72 h and changed twice weekly.25 Utian 26 showed that the Estraderm patches currently used are as efficacious as Premarin in the relief of the symptoms of climacteric and, like Premarin, need to have an added progestogen if endometrial hyperplasia is to be avoided. The area of application of both percutaneous and transdermal systems should be changed regularly because of the possibility of itching and skin irritation. Various preparations are now available with differing modes of delivery. These vary between matrix patches and the original reservoir ones. Increasing numbers of oestrogen and progcstogen patches are now available. Subcutmwous implants Subcutaneous implants have been used to treat the climacteric syndrome for almost 40 years. "7 The technique of insertion is simple and can be done in an outpatients clinic under local anaesthesia. Gonadotrophin levels fall dramatically within 2 weeks

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of implantation and do not return to pretreatment levels before 6 months, if a 100 mg oestradiol implant is used. 28 Similarly, oestradiol levels rise to reach a peak at 2-3 months and are back to pretreatment levels by 6 months in most individuals. The use of subcutaneous hormone implants avoids the need for daily patient compliance. Furthermore, a testosterone pellet (100mg) can be safely inserted and, thus, give the patient further relief of the symptoms of lethargy and loss of libido. Methyltestosterone (which might be useful for the treatment of psychosexual symptoms) is hepatotoxic when administered orally. Implants give good symptomatic relief for up to 6 months, 29 have few side-effects and complications are rare. Even more interesting is the apparent increase in bone mass that is possible in postmenopausal women using oestradiol implant regimes. In a recent study, Savvas et aP° showed that a population of women who had been on oestradiol and testosterone implants for between 2 and I0 years had a higher bone mass than a comparable group who had been on oral therapy, who, in turn, had a bone mass as high as a population of very early postmenopausal women. Furthermore, a prospective study now underway by the same authors is showing a considerable increase in bone mass occurring in women on oestradiol-only implants. A 5% increase in vertebral bone density was found after 6 months, and a 9%increase after 1 year. The conclusion from this and other studies is that, although it is possible to maintain bone mass using oral preparations, the higher oestradiol levels achieved with a subcutaneous oestradiol/testosterone implant will lead to a gain in bone mass and a reversal in bone loss. Similar results are obtained when collagen content and thickness of skin is studied when women receive oestradiol implantsY'The oral preparations currently used can only increase bone mass in early postmenopausal women if they are combined with pharmacological doses of an antiresorptive agent such as calcitonin? 3 This would entail at least two injections a week. It has also been shown that oestradiol and testosterone implants are also effective in increasing bone mass in older women (over 65 years), and will also retain its protective properties in preventing bone loss) 4

IMPORTANCE OF OESTROGEN! PROGESTOGEN O P P O S E D THERAPY It has been established that if oestrogens are given on their own and continuously, the incidence of endometrial hyperplasia and the possibility of causing a well differentiated adenocarcinoma of the endometrium is increased, whichever route of administration is used. Assessment of oestrogen concentration within the nuclei of endometrial cells has shown a higher level of

oestradiol than oestrone, ~5so it is likely that oestradiol has a greater effect on cell proliferation. Oral oestrogen may be associated with a lower incidence of endometrial hyperplasia than with other methods. If, in exceptional circumstances, oestrogens need to be used alone, then it would be safer to use such preparations cyclically (i.e. 21 days out of every 28). The addition of cyclical progestogen therapy for 13 days each month has been shown to prevent endometrial hyperplasia? ~'37 In women who do not want cyclical bleeding, or who would be better managed without a monthly withdrawal bleed, it is possible to start continuous regimens of oral oestrogens and combine this with continuous progestogens. By adjusting the progestogen dose appropriately, it is possible to obtain 100% amenorrhoea within 6-9 months of therapy? 7 There is no evidence, however, that any extra benefit or protection is achieved anywhere if gestagens are prescribed in the absence of a uterus? s Indeed, the protective effect of oestrogens on the cardiovascular system might be compromised by gestagens." The prospective effect of gestagens against breast cancer is extremely controversial/° evidence in favour is weak and there is certainly no consensus." GambrelP '"-' has suggested that such a protective effect does exist, but should be considered in conjunction with the evidence of Pike et aP ~on progestogens increasing the incidence of breast cancer. Other authors have not shown any difference in the incidence of breast cancer with women on oestrogens alone when compared to those on combined preparations. '~

CONTRAINDICATIONS TO H O R M O N E R E P L A C E M E N T THERAPY As with all treatment, oestrogen therapy requires consideration of the severity of the illness to be treated and the possible side-effects. Most workers would accept that breast carcinoma and endometriat carcinoma are contraindications, but scientific support for these objections is hard to find. It is not unusual that women with oestrogen-dependent tumours are prepared to take the risk of oestrogen therapy because their lives are made so unbearable by menopausal symptoms. There is, in fact, no evidence that oestrogen therapy produces a recurrence of breast or endometrial carcinoma, but if a recurrence does occur it is likely that oestrogens will be blamed. Hypertension, varicose veins, a previous thrombotic episode, diabetes, endometriosis and fibroids are classically regarded as contraindications, but, once again, there is little evidence that this is so. There is no evidence that natural oestrogens (i.e. oestradiol, oestrone, or oestriol) cause any elevation of blood pressure in normotensive or hypertensive women. 45Natural progesterone taken orally seems to

Current preparations of HRT lower blood pressure in established hypertensives ~+in contradiction to previous belief. Until recently, it was thought that oestrogens do not affect coagulation, fibrinolysis and platelet behaviour, or cause deep vein thrombosis. 46-~ However, in 1996 three linked case-control studies were published 49-5~ that showed a twofold to fourfold increase in the risk of thromboembolism associated with the use of hormone replacement therapy. The absolute risk is, however, still very small and accounts for only a modest increase in morbidity, as the occurrence of this condition is very rare. In fact, an extra risk of around 1 in 5000 users per year for thromboembolic disease and 5 per 100000 women years for pulmonary embolism was quoted. The avoidance of the first-pass liver effect by utilizing percutaneous or subcutaneous routes gives even less reason to suppose that synthesis of coagulation factors from liver should be stimulated. Although synthetic ethinyloestradiol and mestranol are diabetogenic, the natural oestrogens are notf1.5-' Endometriosis and fibroids are certainly responsive to endogenous and exogenous oestrogens. This does not, in practice, represent any clinical problem because treatment can easily be discontinued. Patients who have undergone a hysterectomy for these conditions, with or without oophorectomy, do not have any contraindications for oestrogen therapy. This is particularly true for endometriosis when the women may be quite young and may have suffered a surgical castration for her condition.

PHYTOESTROGENS Phytoestrogens are naturally occurring constituents in many plants. Legumes are particularly rich in oestrogenic isoflavones while cereals are rich in oestrogenic lignans. Pacific rim nations eating a diet rich in soy experience less severe menopausal symptoms, whilst several chronic diseases of menopausal women including breast cancer, colon cancer and atherosclerotic cardiovascular disease have a much lower incidence than in Western countries. Studies are currently being undertaken so as to explore the potential beneficial role of these compounds in reducing the risk of disease in menopausal women. Initial results presented at the 8th International Congress on the Menopause in Sydney~3 indicated cardioprotective benefits without increasing the risk of endometrial and breast cancer in menopausal women. Other studies indicated flush frequency in menopausal women was reduced when women on soy flour were compared to women on wheat flour in a 6-week study?4 Further work will have to be carried out so as to establish the true potential of plant-derived oestrogen- like substances

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CONCLUSION The changes that occur with changing ovarian function, culminating with the menopause, cause profound changes to a woman. Although not all women have the distressing short-term symptoms, all experience an endocrinological-deficiency syndrome leading to multisystem problems, ranging from connective tissue loss to psychological disturbances. The hormone-deficiency state of menopausal women must be recognized. With increasing longevity of the population, and the increase in morbidity and eventual mortality as a result of sex hormone deficiency, the philosophy of who to treat and who not to treat deserves reappraisal. There is a poor correlation between the short-term symptoms and the long-term consequences of the menopause and, therefore, it is not possible to select women for treatment on the basis of their immediate symptomatology alone. A case can be made for the widespread use of sexhormone replacement so as to improve the quality of life and not just its quantity. With continuing developments sex-hormone replacement is becoming increasingly safe, and its benefits are, seemingly, even more extensive than once supposed, especially in the prophylaxis of cardiovascular disease and osteoporosis. Depriving a woman of hormone replacement for spurious or theoretical reasons should be considered very carefully since very often there are no real contraindications. REFERENCES 1. Geist SH, Mintz M. Pituitary radiation for the relief of menopause symptoms. Am J Obstet Gynecol 1937; 33: 643-645 2. Lightman SL, Jacobs AS, Maguire AK. Down regulation of gonadotrophic secretion in post-menopausal women by a superaetive LHRH analogue: lack of effect on menopausal flushing. Br J Obstet Gynaecol 1982; 89:977-980 3. McLaren HC. Vitamin E in the menopause. BMJ 1949; 2: 1378-1382 4. Clayden JR, Bell JW, Pollard P. Menopausal flushing: double blind trial of a non-hormonal preparation. BMJ 1974; 1: 409-4 ! 2 5. Lindsay R, Hart DM. Failure of response of menopausal vasomotor symptoms of clonidine. Maturitas 1978; 1:21-25 6. Alcoff JM, Campbell D, Tribble D, Oldfield B, Cruess O. Double blind, placebo controlled crossover trial of Propranolol as treatment for menopausal vasomotor symptoms. Clin Ther 1981; 3:356-364 7. Tulandi T, Kinch RA, Guyda H, Mazella L, Lal S. Effect of methyldopa on menopausal flushes, skin temperature and luteinizing hormone secretion. Am J Obstet Gynecol 1984; 150:709-712 8. Haataja M, Paul R, Gronroos M e t al. Effect of prostaglandin inhibitor and estrogen on climacteric symptoms and serum free fatty acids. Maturitas 1984; 5:263-269 9. Patterson MEL. A randomized double-blind cross-over trial into the effect of norethisterone on climacteric symptoms and biochemical profiles. Br J Obstet Gynaecol 1982; 89:464-472 10. Schiff I, Tulchinsky D, Cramer D, Ryan KI. Oral medroxyprogesterone in treatment of postmenopausal s~,Tnptoms. Journal of the American Medical Association 1980; 244:1443-1445 11. Lindsay R, Hart DH, Purdie D, Ferguson M, Clark AS. Comparative effects of oestrogen and a progestogen on bone loss in postmenopausal women. Clinical Science and Molecular Medicine 1978; 54:193-198

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12. Lobo RA, McCormick W, Singer F et al. Depomedroxyprogesterone acetate compared with conjugated oestrogens for the treatment of post-menopausal women. Obstet Gynaecol 1984; 63:!-5 13. Rylance PB, Brincat M, Lafferty K et al. Natural progesterone and antihypertensive action. BMJ 1985; 290:13-14 14. Whitehead M J, Fraser D, Schenkel L, Crook D. Transdermal administration of estrogen/progesterone hormone replacement therapy. Lancet 1990; 335:310-312 15. Chestnut CHIII, Ivey JL, Nelp WB et al. Assessment of anabolic steroids and caleitonin in the treatment of osteoporosis. In: Bar-zel US (ed.) Osteoporosis II. New York: Grune and Stratton 1979; 135-150 16. Ryan KL Engel LI. The interconversion of oestrone and estradiol by human tissue slices. Endocrinology 1953; 52: 287-291 17. Campbell S, Whitehead MI. Potency and hepato-cellular effects of oestrogens after oral, percutaneous and subcutaneous administration. In: Van Keep PA, Utian W, Vermeulen A (ed.) The Controversial Climacteric. Lancaster: MTP Press 1982; 103-125 18. Brenner PM, MashChak CA, Cobo RA et al. Potency and hepato-cellular effects of oestrogen after oral, pereutaneous, subcutaneous administration. In: Van Keep PA, Utian W, Vermular A (eds`) The Controversial Climacteric. Lancaster: MTP Press 1982; 103-125 19. Gordon T, Castelli WP, Hjorteand MC, Kannal WO, Dauber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977; 62:707-714 20. Van der Meer J, Stoepman van Dalen EA, Jensen JMS. Antithrombin III deficiency in a Dutch family. J Clin Pathol 1973; 26:532-538 21. Whitehead MI, Mirandi J, Kitehin Y, Sharples MI. Systemic absorption of estrogen from Premarin vaginal cream. In: Cooke ID (ed.) The role of estrogen/progestogen in the management of the menopause. Lancaster: MTP Press ! 978; 63 -7 ! 22. Schiff I, Tulchinsky D, Ryan KJ. Vaginal absorption of estrone and 17B oestradiol. Fertility and Sterlity 1977; 28: 1063-1065 23. Brincat M, Moniz C, Kabalan Set al. Skin collagen changes in postmenpausal women treated with oestradiol gel. Maturitas 1987; 9:1-5 24. Lyrenas S, Carlstom K, Backstrom T, van Schoultz B. A comparison of serum estrogen levels after pereutaneous and oral administration of oestradiol-17B. Br J Obstet Gynaecol 1981; 83:181-187 25. Vickers CFtt. Reservoir effect of human skin: pharmacological speculation. In: Mautais Jarvis P, Vickers CFH, WePierie J (eds.) Percutaneous absorption of steroids. London: Academic Press 1980; 19-20 26. Utian WH. Alternative delivery systems for steroid hormones. In: Zichella L, Whitehead MI, Van Keep PA (ed.) The climacteric and beyond. New Jersey: Parthenon Publishing Group 1987; 169-183 27. Greenblatt RB, Buran RR. Indications for the hormone pellets on the therapy of endocrine and gynaecological disorders. Am J Obstet Gynaecol 1949; 47:294-301 28. Thom MH, Collins WP, Studd JWW. Hormone profiles in postmenopausal women after therapy with subcutaneous implants. Br J Obstet Gynaecol 1981; 88:426-433 29. Brincat M, Magos AL, Studd JWW et al. Subcutaneous hormone implants for the control of climacteric symptoms: a prospective study. Lancet 1984; i: 16-18 30. Savvas M, Studd JWW, Fogelman I, Dooley M, Montgomery J, Murby B. Skeletal effects of oral oestrogen compared with subcutaneous oestrogen and testosterone in postmenopausal women. British Journal of Medicine 1988; 297:331-333 31. Brincat M, Versi E, Studd JWW et al. Skin collagen changes in postmenopausal women receiving different regimes of oestrogen therapy. Obstet Gynaecol 1987a; 70:123-127 32. Brincat M, Wong A, Studd JWW et al. The response of skin thickness and metacarpal index to oestradiol therapy in postmenopausal women. Obstet Gynaecol 1987b; 70:538-541 33. Meschia M, Brincat M, Barbacini P, Maini MC, Marri R, Crosignani PG. Effect of hormone replacement therapy and calcitonin on bone mass in menopausal women. Eur J Obstet

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Current preparations of HRT 54. Wilcox G. Effect of soy on menopausal symptoms. Proceedings of the 8th International Congress on the Menopause, 3-7 November 1996 Sydney Australia. Maturitas 1997; 27 (supp 13)

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