PULSATILE CONTROL OF REPRODUCTION

382

(both

motor and sensory), might in theory reduce muscle inhibition, but there is no direct evidence that this is so. There are a few clinical trials of methods of rehabilitating weakened quadriceps muscles after medial meniscectomy: quadriceps exercises under the supervision of the physiotherapist did not produce results than better unsupervised quadriceps contraction exercises; 16 nor was any advantage demonstrated by the addition of transcutaneous motor stimulation to quadriceps contraction regimens in two studies,17,18 although there was in another smaller one. 19 An alternative approach is to use feedback to enhance quadriceps electromyographic muscle function. This enhances both the electrical output (via an integrated electromyogram) of the wasted quadriceps and its strength.2O Continuous passive movement (CPM) has become a popular method of rehabilitating joint injuries in North America, but no satisfactory clinical trial of its efficacy has been done.21 There is evidence that CPM speeds the disappearance ofhaemarthroses and aids the repair of articular cartilage injuries in rabbits.22,23 It would be of interest to know if this technique has any measurable effect on arthrogenic muscle inhibition. Presumably the biological advantage of muscle inhibition lies in the protection of the injured joint capsule from further injury, just as neurological mechanisms prevent a healing fracture from being overloaded.24 The rapid advance in arthroscopic surgery of the knee joint owes much to the speed of clinical recovery of knee joint function after the operation. 25 Stokes and YoungZ cite unpublished observations that muscle inhibition is less after arthroscopic than after open meniscectomy. It is harder to understand why it should take so long for a wasted and inhibited quadriceps muscle to recover its full bulk and function after joint injury. It may well be worthwhile to devote more attention to the mode of healing of the injured joint capsule, to how the load on the damaged capsule is measured, and to how it recovers its normal neurological activity. Patients whose muscle inhibition and wasting persists inexplicably after apparently minor joint injury remain major clinical problems of rehabilitation. DP, Frost CEB Cost effectiveness study of outpatient physiotherapy after meniscectomy. Br Med J 1982; 284: 485-87. 17. Laughmann RK, Youdas JW, Garrett TR, Chao EYS Strength changes in the normal quadriceps femoris muscle as a result of electrical stimulation. Phys Ther 1983; 63: 16. Forster

medial

494-99.

JF, Semple JE. Comparison of selective strengthening techniques for normal quadriceps. Physiother Can 1983, 35: 300-04 Gould N, Donnermayer D, Gammon GG, et al. Transcutaneous muscle stimulation to retard disuse atrophy after open meniscectomy. Clin Orthop 1983, 178: 190-96. Krebs DE. Clinical electromyographic feedback following meniscectomy a multiple

18 Kramer

19. 20.

regression experimental analysis Phys Ther 1981; 61: 1017-21 Frank C, Akeson H, Woo SL-Y, et al Physiology and therapeutic value of passive joint motion Clin Orthops 1984, 185: 113-25 22 O’Driscol SW, Kumar A, Salter RB The effect of continuous passive motion on the 21

clearance of a haemarthrosis from a synovial joint an experimental investigation in the rabbit Clin Orthop 1983; 176: 305-11. 23. Salter RB, Simmonds DF, Malcolm BW, et al. The biological effect of continuous passive motion on the healing of full thickness defects in articular cartilage: an experimental investigation in the rabbit. J Bone Jt Surg 1980; 62A: 1232-51 24. Meggitt BF, Juett DA, Smith DA, Smith DJ. Cast-bracing for fractures of the femoral shaft. a biomechanical and clinical study. J Bone Jt Surg 1981, 63B: 12-23 25 Northmore-Ball MD, Dandy DJ, Jackson RW. Arthroscopic, open partial, and total meniscectomy; a comparative study J Bone Jt Surg 1983, 65B: 400-04.

PULSATILE CONTROL OF REPRODUCTION TEMPORAL changes in hormone secretion on a scale from circhoral (or ultradian) through circadian, menstrual, seasonal to age-related are well recognised, especially in reproduction. A fascinating aspect of the neuroendocrine regulation of reproduction to have emerged in the past decade is the pulsatile nature of hormone secretion. Evidence for this was first obtained by Knobil and his colleagues in the rhesus monkey in about 1970, and has since been extended to many species. The pulse generator is in the central nervous system-in the medial basal region of the hypothalamus. It works by a synchronous firing of entire populations of endocrine neurons, which discharge a quantum of the decapeptide gonadotropin-releasing hormone (GnRH) into the portal blood capillaries which then carry it to the anterior

pituitary gland. In man, episodic secretion of pituitary gonadotropins, especially luteinising hormone (LH), is considered to imply a preceding pulsatile GnRH stimulus also, though this cannot be observed directly. This LH pattern is characterised by discrete bursts (pulses) separated by periods of little or no secretion and is observable

at

all stages and

states

of

reproductive life, being most evident at high secretion rates (eg, at mid-cycle and after the menopause). The pulse frequency is important and leads to the possibility of physiological and pharmacological control of pituitarygonadal function by frequency modulation. Physiologically, pulses of LH secretion occur every 1-2 h. This frequency may be influenced by gonadal steroids:2,3 thus the LH pulse frequency is higher in the late follicular phase(a time of high oestrogen secretion) and lower in the mid-luteal phase (with high progesterone secretion).2,4 Amplitude modulation by, for example, oestradiol, may also occur but it is more difficult to envisage a neuronal mechanism for this. The need for pulsatility in therapeutic GnRH stimulation of the pituitary has also been established following the early days of GnRH therapy when both constant and infrequent (up to three times daily) administration were found to be ineffective. Pulsatile GnRH therapy through portable pumps delivering small doses subcutaneously or intravenously every 1-2 h has now been successfully applied to the treatment of anovulatory infertility,6-12 male 1. Knobil E. The neuroendocrine control of the menstrual cycle. Recent Progr Hormone Res 1980; 36: 53-88. 2 Yen SSC, Tsai CC, Naftolin F, Vandenberg G, Ajabor L. Pulsatile patterns of gonadotropin release in subjects with and without ovarian function J Clin Endocrinol Metab 1972; 34: 671-75 3. Santen RJ, Bardin CW. Episodic luteinizing hormone secretion in man. J Clin Invest 1973; 52: 2617-28 4. Backstrom CT, McNeilly AS, Leask RM. Baird DT. Pulsatile secretion of LH, FSH, prolactin, oestradiol and progesterone during the human menstrual cycle. Clin Endocrinol 1982; 17: 29-42 5. Nillius SJ. Gonadotrophin-releasing hormone for induction of ovulation in women In’ Hafez ESE, ed. Human ovulation. Amsterdam North Holland, 1979; 385-404 6 Leyendecker G, Wildt L, Hansmann M Pregnancies following chronic-intermittent (pulsatile) administration of GnRH by means of a portable pump (’Zyklomat’) a new approach to the treatment of infertility in hypothalamic amenorrhea J Clin Endocrenol Metab 1980; 51: 1214-16. 7. Crowley WF, McArthur JW. Stimulation of the normal menstrual cycle in Kallman’s syndrome by pulsatile administration of luteinizing hormone-releasing hormone J Clin Endocrinol Metab 1980; 51: 173-75. 8 Reid RL, Leopold GR, Yen SSC. Induction of ovulation and pregnancy with pulsatile luteinizing hormone-releasing factor: Dosage and mode of delivery. Fertil Steril 1981, 36: 553-59. 9. Shoemaker J, Simons AHM, van Osnabrugge GJC et al. Pregnancy after prolonged administration of LHRH in a patient with clomiphene resistant secondary amenorrhea. J Clin Endocrimol Metab 1981, 52: 882-85. 10 Keogh EJ, Mallal SA, Giles PFH, Evans DV. Ovulation induction with intermittent subcutaneous LHRH. Lancet 1981, 1: 147. 11. Skarin G, Nillius SJ, Wide L. Pulsatile low dose LHRH treatment for induction of follicular maturation and ovulation in women with amenorrhoea Acta Endocrinol 1982, 101: 78-86 12 Mason P, Adams J, Morris DV et al Induction ofovulation with pulsatile luteinizing hormone releasing hormone. Br Med J 1984; 288: 181-85

383

hypogonadism,I3,14

,

and the initiation of

puberty.ls,16

One

interesting feature of the induction of ovulation with GnRH, analogous to the earlier findings in the rhesus monkey, is that the massive preovulatory surge of LH secretion occurs despite an unchanging GnRH pulse frequency or amplitude, though this does not necessarily mean that the same is true

physiologically. Supraphysiological GnRH stimulation, whether through increased frequency or amplitude or use of the "superactive" agonist analogues, produces a seemingly paradoxical inhibition of gonadotropin secretion.17,18 Although a postreceptor effect has been proposed 19 the mechanism appears to be a "down-regulation" of the GnRH receptors. 1,18,20. Normally, the gaps between the physiological pulses allow time for receptor recycling or regeneration. This inhibitory effect has led to an expanding range of applications for the GnRH agonists.in situations where a specific (and temporary, if required) reduction or abolition of gonadotropin secretion is beneficial. 17,18 These applications include contraception (both male and female) and the management of endometriosis, precocious puberty, and sex-hormonedependent cancers (such as those of breast and prostate). For the gonads, too, pulsatile stimulation may be important. In the testis, a pulsatile pattern of LH initiates and maintains LH receptors and steroidogenesis whereas single large doses lead to end-organ desensitisation with loss of LH receptors,21adown-regulation phenomenon similar to that concerning GnRH and the pituitary. For the gonads, however, pulsatile therapy is not necessary since large doses and infrequent administration (eg, human chorionic gonadotropin in hypogonadal men or follicle-stimulating hormone in anovulatory women) is effective. This is an aspect that may be re-evaluated now that smaller, more convenient, and more robust pumps have been developed.

Further down the line, the pulses initially generated in the hypothalamus become blunter but they can be detected in ovarian oestradiol secretion in the follicular phase4 and progesterone secretion in the luteal phase.4,22 With progesterone secretion in the rhesus monkey the pulses are not always coincident with those of LH:22 they may be caused by changes in ovarian blood flow, or there may be an "ovarian oscillator". The reproductive end-organs may also release hormones in a pulsatile manner. Recent work in domestic animals has shown that the uterus releases prostaglandins in a TW, Corley KP, Kelch RP, Marshall JC. Hypogonadotrophic hypogonadism: Normal responses to low dose pulsatile administration of gonadotropin- releasing hormone. J Clin Endocrinol Metab 1980; 51: 730-38. 14. Donald RA, Wheeler MJ, Sonksen PH, Lowy C. Hypogonadotrophic hypogonadism resistant to hCG and responsive to LHRH: Report of a case. Clin Endocrinol 1982; 18: 385-89. 15. Marshall JC, Kelch RP. Low dose pulsatile gonadotrophin-releasing hormone in Endocrinol Merab anorexia nervosa: a model of human pubertal development. Clin J 1979; 49: 712-18 16. Hoffman AR, Crowley WR. Induction of puberty in women by long-term pulsatile administration of low-dose gonadotrophin-releasing hormone. N Engl Med 1982; J 307: 1237-41. 17. Sandow J, Clayton RN, Kuhl H. Pharmacology of LHRH and its analogues. In. Crosignani P, Rubin BL, eds. Endocrinology of human infertility: New aspects. London: Academic Press, 1981: 221-46. 18 Sandow J Clinical applications of LHRH and its analogues. Clin Endocrinol 1983; 18: 571-92. 19. Smith MA, Perrin MH, Vale WW. Densitisation of cultured pituitary cells to gonadotrophin-releasing hormone. evidence for a post-receptor mechanism. Mol Cell Endocrinol 1983; 30: 85-96 20 Clayton RN, Catt KJ. Gonadotropin-releasing hormone receptors: Characterization, physiological regulation and relationship to reproductive function Endocr Rev 1981; 2: 186-209 21. Catt KJ, Harwood JP, Clayton RN, et al. Regulation of peptide hormone receptors and gonadal steroidogenesis. Recent Progr Hormone Res 1980; 36: 557-622. 22. Healy DL, Schenken RS, Lynch A, Williams RF, Hodgen GD. Pulsatile progesterone secretion its relevance to clinical evaluation of the corpus luteum Fertil Steril 1984; 41: 114-21.

13 Valk

pulsatile manner which is controlled by pulses of oxytocin presumed to be from the brain.23 This is related to episodic regeneration of oxytocin receptors which is in turn oestrogendependent. Pulsatile hormone production thus has its origins in the brain but the effects are seen throughout the reproductive system. The unravelling of this neuroendocrine axis has been exciting and it has lately been turned on its head by the unexpected finding of substantial amounts of "brain hormones" (such as oxytocin and GnRH-like peptides) as well as receptors for them in the gonads,24,25 though their significance remains to be established. COTSIDES—PROTECTING WHOM AGAINST WHAT? IN the hagiology of British geriatric medicine those who first proscribed the routine use of cotsides for elderly patients in hospital rank with the liberal spirits of the 18th century who struck off the fetters from patients in lunatic asylums. It is therefore with an element of shock that we learn, 30 years later, that in the United States of America use of cotsides is still routine practice for hospital patients aged more than 65 or 70. Rubenstein et al,’ writing from the University Health Services at Harvard, present a stimulating review of some of the medical, legal, and ethical issues. As with so much that is absurd or distasteful about North American medical practice, the blame lies more with the abuse of litigation than with the callousness of doctors. If an elderly patient in the USA falls out of bed when cotsides have not been in position subsequent litigation can be expected to conclude that care has been negligent. The use of cotsides is taken by lawyers to indicate that the hospital has made an effort to protect the patient. Ironically, although the effort may prevent successful litigation it is unlikely to benefit the patient. When used with a confused or restless patient, cotsides probably do not diminish his risk of falling, may increase his confusion and distress, and certainly ensure, whether he is confused or lucid, that if he does fall it will be from a greater height. Rubenstein et al record that in 14 out of 16 falls associated with getting out of bed the patient was climbing over the cotsides, and, where the information was available, his purpose was a visit to the toilet or some other legitimate errand. In Britain, where cotsides are rarely and selectively used, hospital fall-fracture rates are lower than in the United States. American physicians face the task of persuading lawyers and insurance commissioners to conceive it possible that a measure assumed to improve safety might actually increase hazards. It is suggested that a randomised controlled trial of cotsides might achieve this. This proposal raises interesting ethical and legal issues. One difficulty is that, once lawyers have been allowed to define what is good medical practice, reevaluation becomes practically impossible since a doctor cannot, without fear of litigation, allocate patients to a treatment which the courts have decreed to be inferior-even if there is no scientific evidence to support that view. Can it even be assumed that courts would necessarily respect 23 Schramm

W, Bovaird L, Glew ME, Schramm G, McCracken JA. Corpus luteum by ultra-low pulses of prostaglandins F2 alpha. Prostaglandins

repression induced 1983; 26: 347-61

24. Wathes DC, Swann RW, Birkett SD, Porter DG, Pickering BT. Characterization of oxytocin, vasopressin and neurophysin from the bovine corpus luteum. Endocrinology 1983; 113: 693-98. 25. Sharpe RM. The hormonal regulation of the Leydig cell In: Finn CA, ed. Oxford reviews of reproductive biology: Vol IV. Oxford: Clarendon Press, 1982. 241-317. 1. Rubenstein HS, Miller FH, Postel S, Evans HB Standards of medical care based on consensus rather than evidence the case of routine bedrail use for the elderly Law Med Health Care 1983; 11: 271-76