M. BKINCAT, A. MAGOS, J. W, W. Sri’ini, L. D. CARDOZO, T. O’Dowd, P. J. Wardle
Summary
55 postmenopausal women on established hormone replacement therapy were treated with either ocstradiol and testosterone implants or placebo at the time of return ofclimacterie symptoms. Their response to therapy was assessed prospectively. Ther statistically highly significant levels of symptom relief that followed an ocstradiol and icstoserone implant were contrasted sharply with the lack of any significant relief with placebo. Despite the success of ocstradiol and testosterone implants in relieving symptoms of the climacteric, symptoms returned once the treatment was stopped. Evidence is presented that it is the fall in hormone levels rather than the level itself that provokes the return of climacteric symptoms.
Introduction
Tut; use of subcutaneous implants as an alternative route of oest rogen administration in the climacteric was pioneered by Creenblatt.1 Implants bypass the intestine, avoiding the firstpass effect on liver metabolism of the hormone. This prevents the unphysiological ratio of oestradiol to oestrone found with oral preparations.2 Oral preparations, unlike implants, also reduce liver metabolism of clotting factors and lipids.3
Although interest in implant therapy is increasing, it has still not gained the acceptance of oral therapy and very little prospective work has been done on this route of administration. Implantation is a simple outpatient procedure carried out under local anaesthesia, and it is normally repeated every 6 months.4 Our policy is to insert a pellet of testosterone 100 mg (T) in addition to a pellet of ocstradiol 50 mg (E) in women who complain of coexistent lethargy, depression, and loss of libido.
The few side-effects of E+T implant therapy have been described elsewhere.5 An unexpected finding was that when the symptoms returned after 4 to 6 months, the oestradiol and testosterone levels had fallen only to within the normal premenopausal range. It was therefore considered necessary to compare the effects of placebo treatment on these patients at the time of return of climacteric symptoms.
Patients and methods
55 postmenopausal women were recruited from the Dulwich menopause clinic. All were regular attenders at the clinic and had previously received implants that gave them good relief from their climacteric symptoms (table I).
Table I. Implant history of study population.
Patients were randomly divided into two groups depending on their hospital number. Those with an even case sheet number were given E+T, and those with an odd number were given placebo Norethisteronc 5 mg daily for 7 days each cycle was given to all patients with a uterus to prevent endometrial hyperplasia.2,6,7
There was no significant difference in the average age and weight between the two groups (table II). Patients were not aware of which implant they were receiving. They were asked to score a symptom list using a five-point scale. They were then followed up at 2-month intervals for 8 months. The symptoms assessment sheet was completed by the patients at each visit. They were not allowed to see their previous assessment sheets. Though a repeat implant was offered at 6 months, the women were encouraged to persist without any additional treatment at any other time. However, if they demanded treatment within 6 months, an implant of E+T was always given. If a patient was satisfied at 6 months and insisted that her previous implant was still giving her adequate relief, she was not given a repeat. For each patient a comparison was made for each individual symptom, and the total sum of all symptoms, between her score at month 0 and month 2, month 0 and month 4, month 0 and month 6, and month 0 and month 8. Patients who required treatment at any stage were not considered in the subsequent analysis.
Table II. Patient data.
Statistical Methods
The significance levels were calculated.with the Wilcoxon rank test, a non-parametric test. The results were analysed by the Department of Medical Statistics, King’s College Hospital Medical School, with the statistical package for social sciences.
Results
The symptom responses to the active implant and the placebo implant are shown on tables III and IV.
Table III. Symptom changes with oestradiol 50 mg +testosterone 100 mg* (N = 33).
With the active implant there was a statistically significant improvement in all symptoms investigated except “aches and pains”, and there was an improvement of only short duration in the urethral syndrome. At 6 months the symptom scores had returned to non-significance in six of the symptoms; a significant improvement was maintained only in flushes, headaches, irritability, insomnia, depression, and lethargy.
None of the 33 patients who had received an ,implant of E + T requested a repeat implant at 2 months or at 4 months. 24 (72 • 7%) who were offered one at 6 months accepted, but 9 patients did not need further treatment at that time.
There was no change in symptoms in the patients receiving placebo implants (table IV) at 2, 4, or 6 months. 2 patients insisted on having repeat implants at 2 months and another 5 at 4 months because they were not receiving adequate relief from placebo compared with their previous implants. By 6 months only 15 patients were left in the placebo group. They were then offered a repeat implant, and all but 4 accepted.
Table IV. Symptom changes with placebo.*
Discussion
The statistically highly significant levels of symptom relief that followed an oestradiol and testosterone implant contrast sharply with the lack of significant relief obtained, with placebo at any of the times studied. The only exception to the significant levels of symptom relief with E + T Were the muscular “ aches and pains”, of which many postmenopausal women complain. This finding suggests that this symptom is probably not due to hypo-oestrogenism.
Our results leave little doubt about the superiority of the E + T implant over placebo. They show the efficacy of this treatment in relieving,symptoms of the climacteric, and they demonstrate that symptoms return once the oestrogen is stopped.
Thom et al8 showed that mean oestradiol, oestrpne, and testosterone levels fell between month 4 and month 6 by 32%, 29%, and 39% respectively, in contrast to the rise in these hormone levels between months 0 and 2 and the steady level between months 2 and 4. Cardozo et al5 showed that 6 months after repeat E+T implants, oestradiol, oestrone, and testosterone levels were still well within the premenopausal range and that symptoms returned when oestrogen levels fell from moderately high levels to within the normal premeno¬pausal range. These symptoms were relieved with active therapy and did not respond to placebo.
This indicates that common climacteric symptoms occur in response to a fall in oestrogen levels rather than actual hypo- Oestrogenism and that hormone therapy is effective , in the treatment of these real symptoms regardless of the actual blood hormone levels. This probably explains the frequency and severity of the climacteric symptoms in women approaching the menopause9 despite regular periods and oestrogen levels in the normal range. The failing ovary of these patients is indicated, however, by high levels of follicle- stimulating hormone.10
The rate at which an implant wears off can also be deduced. The active period has been described as being 6 months, and this figure corresponds to that given to us retrospectively by our patients (table I). However, prospectively at 4 months, in our series of patients on E + T, the improvement in the urethral syndrome loses its significance. By 6 months, a total of six symptoms lose their statistical significance, when compared to the severity of symptoms at month 0. In addition, the overall improvement of the total sum of all symptoms loses its significance.
On this information, a case could be made for offering a repeat E + T implant every 4 months instead of every 6 months.
References
Grcenblatt RB, Duron RR. Indications for hormone pellets in ihe therapy of endocrine and gynaecological disorders. J Obstes Gynaccol Br Emp 1949; 57: 294-301.
Thom MH, Studd JWW, Oestrogen and testosterone implant therapy. In: Whitehead M, Campbell S, eds. Oestrogen and the menopause. Queenborough, Kent: Abbott Laboratories Ltd, 1978: 85-88.
Elkik F, Compel A, Mauvais-Jarvis P. Potency and hepatocellular effects ofoestrogens after oral, percutaneous and subcutaneous administration. In: Van Keep PA, Utian W, Vermulen A, eds. The controversial climacteric. Lancaster: MTP Press, 103-25.
Thom MH, Studd JWW. Hormone implantation. Br Med J 1980; i: 848-50.
Cardozo L., Gibb DMF, Tuck SM, Thom MH, Studd JWW. The effects of subcutaneous hormone implants during the climacteric. Maturitas (in press).
Thom MH, White l’J, Williams RM, Sturdcc DW, Paterson MEC, Wadc-Evans T, Studd JWW. Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. Lancet 1979; ii: 455-57.
Studd JWW, Thom MH. Ovarian failure and ageing. Clin Endocrinol Metab 1981; 10; 89-113.
Thom MH, Collins WP, Studd JWW. Hormonal profiles in post-menopausal women after therapy with subcutaneous implants. Br J Obstet Gynaecol 1981; 88: 426-33.
Jaszmann L, Epidemiology of climacteric complaints. Front Harm Res 1973; 2: 220-34.
Chakravati S, Collins WP, Forecast JD, Newton JR, Oram pH, Studd JWW. Hormonal profiles after the menopause. BrMcdJ 1976; ii: 784-86.