- Email: [email protected]
LHRH Analogues for Contraception
1179
of suppression is also dose-related and increased by frequency of administration, so that
degree
depot formulations, given by subcutaneous injection provide continuous release, produce the most sustained profound suppression.5 The simplest approach for LHRH analogue contraception in women is to administer agonists daily throughout the cycle to prevent ovulation. In trials in Sweden, West Germany, and the USA over 200 women have used the agonist buserelin or the more
to
LHRH Analogues for Contraception OVARIAN function, spermatogenesis, and the production of sex steroid hormones are dependent on appropriate stimulation from the anterior pituitary gland hormones luteinising hormone (LH) and follicle-stimulating hormone (FSH). These hormones, in turn, are controlled by the decapeptide luteinising hormone releasing hormone (LHRH), which is released from the hypothalamus in pulses every 1-2 h in amounts controlled by feedback of the sex steroid hormones. Development of LHRH analogues has produced two ways of "switching off" the pituitary gonadal axis. Antagonistic analogues can block the action of LHRH by preventing activation of its receptor, but the high doses required have restricted clinical application.1 Several years ago it was observed that repeated administration of small amounts of LHRH agonist had a "paradoxical" inhibitory effect on ovulation.2 Once daily administration of an LHRH agonist overrides the normal pulsatile gonadotropin profile and reduces the FSH response, so that follicular recruitment and development are disrupted. The pituitary becomes desensitised, there is no LH surge, and ovulation is prevented. Thus, the agonists down-regulate pituitary LHRH receptors and inhibit post-receptor events, leading to a decrease in normal synthesis and release of biologically active gonadotropins.1,3 LHRH agonists have been regarded as a possible alternative hormonal method of contraception. Their advantage over steroidal contraception (which is unacceptable to 10-20% of women) is that they have no direct effects on peripheral target organs such as the cardiovascular system or the liver. Because LHRH analogues are broken down by gastrointestinal enzymes, they must be given by injection or nasal spray.4 The more potent the agonist, the more suppressive the effect on gonadal steroidogenesis. The 1. Fraser
HM, Baird DT. Clinical applications of LHRH analogues. Baillière’s Clin Endocrinol Metab 1987; 1: 23-70 2. Bergquist C, Nillius SJ, Wide L. Intranasal gonadotropin-releasing hormone agonist as a contraceptive agent. Lancet 1979; ii: 215-17. 3 Clayton RN. Gonadotropin releasing hormone: from physiology to pharmacology. Clin Endocrinol 1987; 26: 361-84. 4 Petri W, Seydel R, Sandow J. A pharmaceutical approach to long-term therapy with peptides. In: Labrie F, Belanger A, Dupont A, eds. LHRH and its analogues. Amsterdam: Elsevier, 1984: 63-76.
potent nafarelin for 6-27 months.6-1O In more than 50% of cases the agonist was the sole method of contraception and none of the women became pregnant. When treatment was stopped, ovulatory cycles returned without undue delay. In women taking buserelin, 25 % had amenorrhoea, 37 % regular menstrual-like bleeds, and 38 % oligomenorrhoea, but none had features of dysfunctional uterine bleeding. Nafarelin treatment was more suppressive, with amenorrhoea developing in 75 % of women. This individual variation in bleeding patterns poses practical problems. Irregular bleeding, which is caused by fluctuating oestrogen production without an increase in progesterone, is unacceptable to most women. Initially there was concern that this condition could lead to endometrial hyperplasia, but endometrial biopsies from over 100 women showed that signs of endometrial overstimulation occurred only during the first few months;6,9,10 thereafter, the endometrium showed a weak proliferative picture. Amenorrhoea, caused by oestrogen suppression, removes an important sign which assures the woman that she is not pregnant. However, provided contraceptive efficacy had been established, amenorrhoea would be seen as an advantage by many women.
The main problem with suppressed oestrogen production is symptoms of oestrogen deficiency, such as hot flushes and vaginal dryness. These side-effects depend on the dose and potency of the agonist.6-10 With long-term oestrogen deficiency, there is also the possibility of loss of bone mineral. Abdalla and colleagues have shown that resumption of normal oestrogen production leads to replacement of bone mineral after up to 3 years of absence of oestrogen,l1 5 Walker
KJ, Turkes A, Williams MR, Blarney RW, Nicholson RI. Preliminary endocrinological evaluation of a sustained-release formulation of the LH-releasing hormone agonist D-Ser But)6 Azgly10 LHRH in premenopausal women with advanced breast cancer J Endocrinol 1986; 111: 349-53. 6. Nillius SJ, Bergquist C, Gudmundsson JA, Wide L. Superagonists of LHRH for contraception in women. In. Labrie F, Belanger A, Dupont A, eds LHRH and its agonists. Amsterdam: Elsevier, 1984. 261-74. M, Hardt W, Schmidt-Gollwitzer K. Influence of the LHRH analogue buserelin on cyclic ovanan function and on endometrium. A new approach to fertility control? Contraception 1981; 23: 187-95. 8. Brenner PF, Shoupe D, Mishell DR Jr. Ovulation inhibition with nafarelin acetate nasal administration for six months. Contraception 1985; 32: 531-51 9 Monroe SE, Blumenfeld Z, Andreyko JL. Schriock E, Henzl MR, Jaffe RB. Dose-dependent inhibition of pituitary-ovarian function during administration of a gonadotropin-releasing hormone agonist analog (nafarelin). J Clin Endocrinol Metab 1986; 63: 1334-41. 10. Gudmundsson JA, Nillius SJ, Bergquist C. Intranasal peptide contraception by inhibition of ovulanon with the gonadotropin-releasing hormone superagonist 7. Schmidt-Gollwitzer
nafarelin: six months’ clinical results. Fertil Steril 1986; 45: 617-23. H, Hart DM, Lindsay RL. Differential bone loss and effect of long-term estrogen therapy after oophorectomy. In: Christiansen C, et al, eds. Osteoporosis. Aaalborg: Stittsbottrykkeri, 1984: 621-23
11. Abdalla
1180
but the precise relation between oestrogen and bone mineral is unknown. LHRH agonists, when used for contraception, should be prescribed in the minimum effective dose for ovarian suppression; if signs of oestrogen deficiency arise, the dose should be reduced. The second approach to female contraception is to combine the agonist with a progestagen in a cyclic regimen (eg, buserelin nasal spray for days 1-22, and a progestagen for days 16-22 of the treatment cycle for secretory transformation of the endometrium).12,13 Follicular maturation occurs in the treatment-free interval of 7 days before the start of the next contraceptive cycle and allows oestrogen to be produced, preventing any risk of osteoporosis. The progestagen establishes regular menses and removes any risk of endometrial hyperplasia induced by unopposed oestrogen. However, some women experience mid-cycle bleeding due to oestrogen withdrawal, and introduction of the progestagen, even for a limited period, seems to cause some of the well-known side-effects of steroid oral contraceptives. Use of natural progesterone might overcome this difficulty. Another approach is to use LHRH agonists at selected periods of follicular or luteal development. This technique has yielded some interesting observations but is not a practical method of ensuring an infertile cycle. The development of LHRH agonists for contraception should provide an alternative for women who are unable to find another suitable method and for those over 35, particularly smokers, who run the greatest risk from continuing with combined steroid contraception. Since LHRH agonists can induce amenorrhoea they could also be useful in women with heavy periods. Another indication would be in lactating women; the combined pill cannot be taken during lactation since it will decrease milk yield, while the progestagen-only pill may cause irregular bleeding, which is sometimes unacceptable. LHRH agonists could be used to suppress ovulation during the period of lactationfor example, between 6 weeks and 18 months postpartum.14 The duration of treatment would be short enough to avoid any long-term consequences of low oestrogen production, while the number of women benefiting from adequate birth spacing would be considerable, particularly in developing countries. The small amounts of agonist that appear in the breast milk have no biological effect because of inactivation in the infant’s gut.l4 If successful, use of a long-acting implant releasing small amounts of agonist over several months could be envisaged.
Since LHRH agonists can suppress LH and FSH release, do they have a role in male contraception? Chronic administration can suppress spermatogenesis but the decrease in circulating testosterone levels leads to impaired libido and impotence. Therefore if is LHRH necessary androgen replacement analogues are to be made acceptable for male fertility regulation, 15,16 and this in turn presents a problem in that replacement testosterone reduces the suppressive
effect of agonist on spermatogenesis. Agonist therapy of men with prostatic cancer suppresses testosterone production and spermatogenesis, but younger healthy men are more resistant and azoospermia is seldom achieved. Although it may not be necessary to induce complete azoospermia for effective male contraception, it seems unlikely that use of agonist plus testosterone will have a sufficiently suppressive effect on
spermatogenesis.
LHRH antagonists, which must be given in higher doses than agonists, have a complex structure that makes them expensive to produce. Continued administration of antagonists to male monkeys produces an immediate and more profound inhibition than that of agonists on pituitary FSH and LH release; whilst testosterone replacement is likely to counteract this response to some degree, the effect may be sufficient to achieve an acceptable suppression of fertility. 16,17 In women, antagonists can be used intermittently, rather than continuously, to block specific stages of the ovarian cycle. Intermittent treatment has advantages in that it involves less exposure to the analogue and avoids the potential problem of oestrogen deficiency. However, a method which relies on the woman knowing the stage of her cycle fairly precisely, and which will also lead to cycle disruption, is unlikely to have widespread application.1 What of the future for LHRH analogue contraception? In women, the aim must be to avoid either a hypo-oestrogenic state or unopposed oestrogen. Individual variation has therefore posed a major problem which has not yet been resolved. A better understanding of the role of oestrogen in temperature regulation (hot flushes) and bone metabolism may allow more confident progress. In men, a combination of LHRH antagonist and longacting depot testosterone formulation may sound impracticable, but such work is viewed with optimism, perhaps as a reflection of the dearth of other leads in this area. It is also providing valuable new information about control of spermatogenesis, and should establish whether it is essential to induce Swerdloff RS, Bhasin S. Hormonal effects of GnRH agonist in the human male an approach to male contraception using combined androgen and GnRH agonist treatment. In: Labrie F, Belanger A, Dupont A, eds. LHRH and its analogues Amsterdam: Elsevier, 1984: 287-301. 16 Weinbauer GF, Surmann FJ, Nieschlag E. Suppression of spermatogenesis in a non human primate (Macaca fascicularis) by concomitant gonadotropin-releasing hormone antagonist and testosterone treatment. Acta Endocrinol 1987; 114: 15.
12.
Fauré N. Fourteen-day versus twenty-one-day regimens of intermittent intranasal luteinizing hormone-releasing hormone agonist combined with an oral progestagen as antiovulatory contraceptive approach. J Endocrinol Metab 1986; 63: 1379-85.
Lemay A,
13 Kuhl
H, Jung C, Taubert HD. Contraception with an LHRH agonist effects on gonadotrophin and steroid secretion patterns. Clin Endocrinol 1984; 21: 179-88. 14. Dewart PJ, McNeilly AS, Smith SK, Sandow J, Hillier SG, Fraser HM. LRH agonist buserelin as a post-partum contraceptive: lack of biological activity of buserelin in breast milk. Acta Endocrinol
1987, 114: 185-92
138-46 17. Knuth
UA, Nieschlag E. Endocrine approaches Clin Endocrinol Metab 1987; 1: 113-31.
to
male
fertility control Baillière’s
1181
azoospermia for contraception or whether oligospermia will do. The pharmaceutical industry has taken a considerable interest in the development of slow-release formulations of LHRH analogues last for intervals of 1 or up to 6 months. Whilst these preparations are being used for
programmed
to
therapeutic purposes (eg, endometriosis, fibroids, prostatic carcinoma), their widespread application and acceptance may in turn encourage further research so that the potential benefits of LHRH analogues for contraception can be realised.
management of sensorineural rather than conductive
impairments is the main issue. As the age distribution of the general population shifts upwards, the requirement for treatment of conductive conditions will decline. Surgery may also be less appropriate in elderly individuals for other reasons. In otological practice, conductive conditions comprise between one-third and one-half of referrals. The discrepancy between the population figures and clinic incidence figures for the proportion of people with conductive impairments is due to preferential referral by the patients themselves and perhaps by their primary care physicians. The reasons for this are not entirely clear, but may be related to the fact that some conductive conditions associated with a discharge and are therefore more
are
immediately obvious.
HEARING PROBLEMS IN ELDERLY PEOPLE:
IMPLICATIONS FOR SERVICES disorders in the and their with distribution age have important populationl for rehabilitative services.2 The population implications of conducted hearing irnpainnent3,4 by the Medical survey Research Council’s Institute of Hearing Research gives information on the relative contributions of conductive and sensorineural impairments to the overall prevalence figures at various ages, and also offers the opportunity to examine on a population rather than clinic basis the effectiveness and uptake of services by various potential groups. For a working definition of the degree of hearing impairment requiring management, the average over the four frequencies of 500, 1000, 2000, and 4000 Hz of greater than or equal to 45 dB hearing level (HL) in the better hearing ear is appropriate. Lesser degrees of impairment undoubtedly lead to material disability and can now be managed, but the 45 dB HL approximates the median level at which individuals secure referral for management. Hearing impairment is exponentially related to age: by use of the 45 dB criterion, 2% of 41-50-year-olds, 5% of 51-60-year-olds, 10% of 61-70-year-olds, and 19% of the over 70s have impaired hearing. Unfortunately, the term presbyacusis has been used as a diagnostic label for age-related hearing loss, implying the existence of a specific disease process that could in principle be diagnosed. However, evidence suggests that the increasing hearing loss with age is brought about by cumulative exposure to the diverse insults to which the auditory mechanism may be exposed, possibly coupled with an individually variable, but declining, ability to repair the damage. It is important to establish the proportion of conductive (middle ear) conditions in the hearing-impaired population since management may be surgical rather than by fitting of a hearing-aid or other rehabilitative measures. The percentage of the population with a material (20 dB air-bone gap) conductive component (considering only subjects with a 45 dB overall hearing level) is 1-2%. However, the age distribution of conductive conditions is not uniform: the proportion of conductive conditions is 55% in 41-50-yearolds, declining to approximately 20% in 51-70-year-olds, and to under 7% in the over 70s. Thus with increasing age, THE
1
high prevalence of hearing
Haggard MP, Gatehouse S, Davis AC. The high prevalence of hearing disorder in the population and its implications for services. Br J Audiol 1981; 15: 241-51. 2. Salomon G. Hearing problems and the elderly. Dan Med Bull 1986 (Gerontology, suppl 3). 3. Institute of Hearing Research. Population study of hearing disorders in adults preliminary communication. J R Soc Med 1981; 74: 819-27. 4. Browning GG, Davis AC. Clinical characterization of the hearing of the adult British population. Adv Oto Rhino Laryngol 1983; 31: 217-23.
In addition, most conductive disorders cause asymmetry in hearing levels, and therefore will be more apparent to the patient. One method of assessing uptake of services is to examine the rate at which individuals consult their general practitioner about a particular problem. Thus 95% of 41-50-year-olds who have a hearing level worse than 45 dB in their better hearing ear have at some time sought help. The percentage of those failing the 45 dB criterion falls progressively with age-figures for the 51-60, 61-70, and over 70 age groups are 70%, 59%, and 46%, respectivelyand it is only because the population prevalence climbs so steeply with age that the distribution of clinical populations remains biased towards the elderly. One way of examining the eventual demand on rehabilitative services is to consider the proportion of individuals not qualifying by the 45 dB HL criterion who have at some time tried to use a hearing aid. This proportion declines from 83% in the 41-50 band to only 34% in the over 70s. There may, of course, be many reasons why a hearing aid may not be ultimately tried or offered, and some of these reasons vary with age. The lower prevalence of conductive conditions and possible contraindications for surgery in older people favour hearing aids, but declining physical and mental ability might make a hearing aid less likely to be offered. It is possible to examine the difference between the proportion who have sought help from their general practitioner and the proportion who have ultimately tried a hearing aid. On the basis of this discrepancy the shortfall in service provision is at least three-quarters due to public attitudes (uptake), and, at most, one-quarter due to the attitudes of general practitioners (filtering). (Examples of attitude would be the acceptance of hearing loss with increasing age as a natural course of events, or adjustment of expectations and lifestyle as age increases.) Thus, if the services are to reach those in need, a programme of public rather than medical education is required, aimed predominantly at elderly individuals. Many individuals issued with a hearing aid cease to use it. This proportion can be used both as a measure of the overall effectiveness of the services and of the applicability of the available devices and services for the different groups of disorders or age-bands. Such data reveal an interesting trend. 12% of all 41-50-year-olds who have tried an aid cease to use it; figures for age groups 51-60, 61-70, and over 70 are 32%, 22%, and 28%, respectively. The high percentage in the 51-60-year-olds suggests that middleaged people are not given aids of sufficiently high quality to make any real difference to their hearing ability under the circumstances in which they have to listen. The over 70s may not use the basic hearing aid provided because their more complex requirements are not being met. Thus, future
of suppression is also dose-related and increased by frequency of administration, so that
degree
depot formulations, given by subcutaneous injection provide continuous release, produce the most sustained profound suppression.5 The simplest approach for LHRH analogue contraception in women is to administer agonists daily throughout the cycle to prevent ovulation. In trials in Sweden, West Germany, and the USA over 200 women have used the agonist buserelin or the more
to
LHRH Analogues for Contraception OVARIAN function, spermatogenesis, and the production of sex steroid hormones are dependent on appropriate stimulation from the anterior pituitary gland hormones luteinising hormone (LH) and follicle-stimulating hormone (FSH). These hormones, in turn, are controlled by the decapeptide luteinising hormone releasing hormone (LHRH), which is released from the hypothalamus in pulses every 1-2 h in amounts controlled by feedback of the sex steroid hormones. Development of LHRH analogues has produced two ways of "switching off" the pituitary gonadal axis. Antagonistic analogues can block the action of LHRH by preventing activation of its receptor, but the high doses required have restricted clinical application.1 Several years ago it was observed that repeated administration of small amounts of LHRH agonist had a "paradoxical" inhibitory effect on ovulation.2 Once daily administration of an LHRH agonist overrides the normal pulsatile gonadotropin profile and reduces the FSH response, so that follicular recruitment and development are disrupted. The pituitary becomes desensitised, there is no LH surge, and ovulation is prevented. Thus, the agonists down-regulate pituitary LHRH receptors and inhibit post-receptor events, leading to a decrease in normal synthesis and release of biologically active gonadotropins.1,3 LHRH agonists have been regarded as a possible alternative hormonal method of contraception. Their advantage over steroidal contraception (which is unacceptable to 10-20% of women) is that they have no direct effects on peripheral target organs such as the cardiovascular system or the liver. Because LHRH analogues are broken down by gastrointestinal enzymes, they must be given by injection or nasal spray.4 The more potent the agonist, the more suppressive the effect on gonadal steroidogenesis. The 1. Fraser
HM, Baird DT. Clinical applications of LHRH analogues. Baillière’s Clin Endocrinol Metab 1987; 1: 23-70 2. Bergquist C, Nillius SJ, Wide L. Intranasal gonadotropin-releasing hormone agonist as a contraceptive agent. Lancet 1979; ii: 215-17. 3 Clayton RN. Gonadotropin releasing hormone: from physiology to pharmacology. Clin Endocrinol 1987; 26: 361-84. 4 Petri W, Seydel R, Sandow J. A pharmaceutical approach to long-term therapy with peptides. In: Labrie F, Belanger A, Dupont A, eds. LHRH and its analogues. Amsterdam: Elsevier, 1984: 63-76.
potent nafarelin for 6-27 months.6-1O In more than 50% of cases the agonist was the sole method of contraception and none of the women became pregnant. When treatment was stopped, ovulatory cycles returned without undue delay. In women taking buserelin, 25 % had amenorrhoea, 37 % regular menstrual-like bleeds, and 38 % oligomenorrhoea, but none had features of dysfunctional uterine bleeding. Nafarelin treatment was more suppressive, with amenorrhoea developing in 75 % of women. This individual variation in bleeding patterns poses practical problems. Irregular bleeding, which is caused by fluctuating oestrogen production without an increase in progesterone, is unacceptable to most women. Initially there was concern that this condition could lead to endometrial hyperplasia, but endometrial biopsies from over 100 women showed that signs of endometrial overstimulation occurred only during the first few months;6,9,10 thereafter, the endometrium showed a weak proliferative picture. Amenorrhoea, caused by oestrogen suppression, removes an important sign which assures the woman that she is not pregnant. However, provided contraceptive efficacy had been established, amenorrhoea would be seen as an advantage by many women.
The main problem with suppressed oestrogen production is symptoms of oestrogen deficiency, such as hot flushes and vaginal dryness. These side-effects depend on the dose and potency of the agonist.6-10 With long-term oestrogen deficiency, there is also the possibility of loss of bone mineral. Abdalla and colleagues have shown that resumption of normal oestrogen production leads to replacement of bone mineral after up to 3 years of absence of oestrogen,l1 5 Walker
KJ, Turkes A, Williams MR, Blarney RW, Nicholson RI. Preliminary endocrinological evaluation of a sustained-release formulation of the LH-releasing hormone agonist D-Ser But)6 Azgly10 LHRH in premenopausal women with advanced breast cancer J Endocrinol 1986; 111: 349-53. 6. Nillius SJ, Bergquist C, Gudmundsson JA, Wide L. Superagonists of LHRH for contraception in women. In. Labrie F, Belanger A, Dupont A, eds LHRH and its agonists. Amsterdam: Elsevier, 1984. 261-74. M, Hardt W, Schmidt-Gollwitzer K. Influence of the LHRH analogue buserelin on cyclic ovanan function and on endometrium. A new approach to fertility control? Contraception 1981; 23: 187-95. 8. Brenner PF, Shoupe D, Mishell DR Jr. Ovulation inhibition with nafarelin acetate nasal administration for six months. Contraception 1985; 32: 531-51 9 Monroe SE, Blumenfeld Z, Andreyko JL. Schriock E, Henzl MR, Jaffe RB. Dose-dependent inhibition of pituitary-ovarian function during administration of a gonadotropin-releasing hormone agonist analog (nafarelin). J Clin Endocrinol Metab 1986; 63: 1334-41. 10. Gudmundsson JA, Nillius SJ, Bergquist C. Intranasal peptide contraception by inhibition of ovulanon with the gonadotropin-releasing hormone superagonist 7. Schmidt-Gollwitzer
nafarelin: six months’ clinical results. Fertil Steril 1986; 45: 617-23. H, Hart DM, Lindsay RL. Differential bone loss and effect of long-term estrogen therapy after oophorectomy. In: Christiansen C, et al, eds. Osteoporosis. Aaalborg: Stittsbottrykkeri, 1984: 621-23
11. Abdalla
1180
but the precise relation between oestrogen and bone mineral is unknown. LHRH agonists, when used for contraception, should be prescribed in the minimum effective dose for ovarian suppression; if signs of oestrogen deficiency arise, the dose should be reduced. The second approach to female contraception is to combine the agonist with a progestagen in a cyclic regimen (eg, buserelin nasal spray for days 1-22, and a progestagen for days 16-22 of the treatment cycle for secretory transformation of the endometrium).12,13 Follicular maturation occurs in the treatment-free interval of 7 days before the start of the next contraceptive cycle and allows oestrogen to be produced, preventing any risk of osteoporosis. The progestagen establishes regular menses and removes any risk of endometrial hyperplasia induced by unopposed oestrogen. However, some women experience mid-cycle bleeding due to oestrogen withdrawal, and introduction of the progestagen, even for a limited period, seems to cause some of the well-known side-effects of steroid oral contraceptives. Use of natural progesterone might overcome this difficulty. Another approach is to use LHRH agonists at selected periods of follicular or luteal development. This technique has yielded some interesting observations but is not a practical method of ensuring an infertile cycle. The development of LHRH agonists for contraception should provide an alternative for women who are unable to find another suitable method and for those over 35, particularly smokers, who run the greatest risk from continuing with combined steroid contraception. Since LHRH agonists can induce amenorrhoea they could also be useful in women with heavy periods. Another indication would be in lactating women; the combined pill cannot be taken during lactation since it will decrease milk yield, while the progestagen-only pill may cause irregular bleeding, which is sometimes unacceptable. LHRH agonists could be used to suppress ovulation during the period of lactationfor example, between 6 weeks and 18 months postpartum.14 The duration of treatment would be short enough to avoid any long-term consequences of low oestrogen production, while the number of women benefiting from adequate birth spacing would be considerable, particularly in developing countries. The small amounts of agonist that appear in the breast milk have no biological effect because of inactivation in the infant’s gut.l4 If successful, use of a long-acting implant releasing small amounts of agonist over several months could be envisaged.
Since LHRH agonists can suppress LH and FSH release, do they have a role in male contraception? Chronic administration can suppress spermatogenesis but the decrease in circulating testosterone levels leads to impaired libido and impotence. Therefore if is LHRH necessary androgen replacement analogues are to be made acceptable for male fertility regulation, 15,16 and this in turn presents a problem in that replacement testosterone reduces the suppressive
effect of agonist on spermatogenesis. Agonist therapy of men with prostatic cancer suppresses testosterone production and spermatogenesis, but younger healthy men are more resistant and azoospermia is seldom achieved. Although it may not be necessary to induce complete azoospermia for effective male contraception, it seems unlikely that use of agonist plus testosterone will have a sufficiently suppressive effect on
spermatogenesis.
LHRH antagonists, which must be given in higher doses than agonists, have a complex structure that makes them expensive to produce. Continued administration of antagonists to male monkeys produces an immediate and more profound inhibition than that of agonists on pituitary FSH and LH release; whilst testosterone replacement is likely to counteract this response to some degree, the effect may be sufficient to achieve an acceptable suppression of fertility. 16,17 In women, antagonists can be used intermittently, rather than continuously, to block specific stages of the ovarian cycle. Intermittent treatment has advantages in that it involves less exposure to the analogue and avoids the potential problem of oestrogen deficiency. However, a method which relies on the woman knowing the stage of her cycle fairly precisely, and which will also lead to cycle disruption, is unlikely to have widespread application.1 What of the future for LHRH analogue contraception? In women, the aim must be to avoid either a hypo-oestrogenic state or unopposed oestrogen. Individual variation has therefore posed a major problem which has not yet been resolved. A better understanding of the role of oestrogen in temperature regulation (hot flushes) and bone metabolism may allow more confident progress. In men, a combination of LHRH antagonist and longacting depot testosterone formulation may sound impracticable, but such work is viewed with optimism, perhaps as a reflection of the dearth of other leads in this area. It is also providing valuable new information about control of spermatogenesis, and should establish whether it is essential to induce Swerdloff RS, Bhasin S. Hormonal effects of GnRH agonist in the human male an approach to male contraception using combined androgen and GnRH agonist treatment. In: Labrie F, Belanger A, Dupont A, eds. LHRH and its analogues Amsterdam: Elsevier, 1984: 287-301. 16 Weinbauer GF, Surmann FJ, Nieschlag E. Suppression of spermatogenesis in a non human primate (Macaca fascicularis) by concomitant gonadotropin-releasing hormone antagonist and testosterone treatment. Acta Endocrinol 1987; 114: 15.
12.
Fauré N. Fourteen-day versus twenty-one-day regimens of intermittent intranasal luteinizing hormone-releasing hormone agonist combined with an oral progestagen as antiovulatory contraceptive approach. J Endocrinol Metab 1986; 63: 1379-85.
Lemay A,
13 Kuhl
H, Jung C, Taubert HD. Contraception with an LHRH agonist effects on gonadotrophin and steroid secretion patterns. Clin Endocrinol 1984; 21: 179-88. 14. Dewart PJ, McNeilly AS, Smith SK, Sandow J, Hillier SG, Fraser HM. LRH agonist buserelin as a post-partum contraceptive: lack of biological activity of buserelin in breast milk. Acta Endocrinol
1987, 114: 185-92
138-46 17. Knuth
UA, Nieschlag E. Endocrine approaches Clin Endocrinol Metab 1987; 1: 113-31.
to
male
fertility control Baillière’s
1181
azoospermia for contraception or whether oligospermia will do. The pharmaceutical industry has taken a considerable interest in the development of slow-release formulations of LHRH analogues last for intervals of 1 or up to 6 months. Whilst these preparations are being used for
programmed
to
therapeutic purposes (eg, endometriosis, fibroids, prostatic carcinoma), their widespread application and acceptance may in turn encourage further research so that the potential benefits of LHRH analogues for contraception can be realised.
management of sensorineural rather than conductive
impairments is the main issue. As the age distribution of the general population shifts upwards, the requirement for treatment of conductive conditions will decline. Surgery may also be less appropriate in elderly individuals for other reasons. In otological practice, conductive conditions comprise between one-third and one-half of referrals. The discrepancy between the population figures and clinic incidence figures for the proportion of people with conductive impairments is due to preferential referral by the patients themselves and perhaps by their primary care physicians. The reasons for this are not entirely clear, but may be related to the fact that some conductive conditions associated with a discharge and are therefore more
are
immediately obvious.
HEARING PROBLEMS IN ELDERLY PEOPLE:
IMPLICATIONS FOR SERVICES disorders in the and their with distribution age have important populationl for rehabilitative services.2 The population implications of conducted hearing irnpainnent3,4 by the Medical survey Research Council’s Institute of Hearing Research gives information on the relative contributions of conductive and sensorineural impairments to the overall prevalence figures at various ages, and also offers the opportunity to examine on a population rather than clinic basis the effectiveness and uptake of services by various potential groups. For a working definition of the degree of hearing impairment requiring management, the average over the four frequencies of 500, 1000, 2000, and 4000 Hz of greater than or equal to 45 dB hearing level (HL) in the better hearing ear is appropriate. Lesser degrees of impairment undoubtedly lead to material disability and can now be managed, but the 45 dB HL approximates the median level at which individuals secure referral for management. Hearing impairment is exponentially related to age: by use of the 45 dB criterion, 2% of 41-50-year-olds, 5% of 51-60-year-olds, 10% of 61-70-year-olds, and 19% of the over 70s have impaired hearing. Unfortunately, the term presbyacusis has been used as a diagnostic label for age-related hearing loss, implying the existence of a specific disease process that could in principle be diagnosed. However, evidence suggests that the increasing hearing loss with age is brought about by cumulative exposure to the diverse insults to which the auditory mechanism may be exposed, possibly coupled with an individually variable, but declining, ability to repair the damage. It is important to establish the proportion of conductive (middle ear) conditions in the hearing-impaired population since management may be surgical rather than by fitting of a hearing-aid or other rehabilitative measures. The percentage of the population with a material (20 dB air-bone gap) conductive component (considering only subjects with a 45 dB overall hearing level) is 1-2%. However, the age distribution of conductive conditions is not uniform: the proportion of conductive conditions is 55% in 41-50-yearolds, declining to approximately 20% in 51-70-year-olds, and to under 7% in the over 70s. Thus with increasing age, THE
1
high prevalence of hearing
Haggard MP, Gatehouse S, Davis AC. The high prevalence of hearing disorder in the population and its implications for services. Br J Audiol 1981; 15: 241-51. 2. Salomon G. Hearing problems and the elderly. Dan Med Bull 1986 (Gerontology, suppl 3). 3. Institute of Hearing Research. Population study of hearing disorders in adults preliminary communication. J R Soc Med 1981; 74: 819-27. 4. Browning GG, Davis AC. Clinical characterization of the hearing of the adult British population. Adv Oto Rhino Laryngol 1983; 31: 217-23.
In addition, most conductive disorders cause asymmetry in hearing levels, and therefore will be more apparent to the patient. One method of assessing uptake of services is to examine the rate at which individuals consult their general practitioner about a particular problem. Thus 95% of 41-50-year-olds who have a hearing level worse than 45 dB in their better hearing ear have at some time sought help. The percentage of those failing the 45 dB criterion falls progressively with age-figures for the 51-60, 61-70, and over 70 age groups are 70%, 59%, and 46%, respectivelyand it is only because the population prevalence climbs so steeply with age that the distribution of clinical populations remains biased towards the elderly. One way of examining the eventual demand on rehabilitative services is to consider the proportion of individuals not qualifying by the 45 dB HL criterion who have at some time tried to use a hearing aid. This proportion declines from 83% in the 41-50 band to only 34% in the over 70s. There may, of course, be many reasons why a hearing aid may not be ultimately tried or offered, and some of these reasons vary with age. The lower prevalence of conductive conditions and possible contraindications for surgery in older people favour hearing aids, but declining physical and mental ability might make a hearing aid less likely to be offered. It is possible to examine the difference between the proportion who have sought help from their general practitioner and the proportion who have ultimately tried a hearing aid. On the basis of this discrepancy the shortfall in service provision is at least three-quarters due to public attitudes (uptake), and, at most, one-quarter due to the attitudes of general practitioners (filtering). (Examples of attitude would be the acceptance of hearing loss with increasing age as a natural course of events, or adjustment of expectations and lifestyle as age increases.) Thus, if the services are to reach those in need, a programme of public rather than medical education is required, aimed predominantly at elderly individuals. Many individuals issued with a hearing aid cease to use it. This proportion can be used both as a measure of the overall effectiveness of the services and of the applicability of the available devices and services for the different groups of disorders or age-bands. Such data reveal an interesting trend. 12% of all 41-50-year-olds who have tried an aid cease to use it; figures for age groups 51-60, 61-70, and over 70 are 32%, 22%, and 28%, respectively. The high percentage in the 51-60-year-olds suggests that middleaged people are not given aids of sufficiently high quality to make any real difference to their hearing ability under the circumstances in which they have to listen. The over 70s may not use the basic hearing aid provided because their more complex requirements are not being met. Thus, future