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ENHANCEMENT OF HUMAN IMPLANTATION BY EXOGENOUS CHORIONIC GONADOTROPIN
1191 ENHANCEMENT OF HUMAN IMPLANTATION BY EXOGENOUS CHORIONIC GONADOTROPIN
SIR,-The efficiency of human fertilisation, both natural’ and in about 85%. However, the probability of conception,
vitro,2 is
recognisable by the absence of menses (recognisable fecundability rate), is only 0 -20-0’25 for women under the age of 30.1°3 This difference suggests that implantation of the fertilised ovum is the rate-limiting step in human fertility. An observation by Lenton et al,4 that serum progesterone levels during days 3-8 of the luteal phase were higher in conception cycles than in non-conception cycles, led us to investigate the possibility of enhancing implantation and recognisable fecundability by stimulating corpus luteum function with exogenous human chorionic gonadotropin
(hCG). Women with primary infertility who were receiving artificial insemination with donor sperm (AID) because their husbands were azoospermic or severely oligospermic volunteered for this study. We chose these women because ovulation and tubal patency had been proven and we could control the timing of insemination. A randomised, double-blind controlled study was done at two university centres with established artificial insemination programmes. Most patients received two inseminations with fresh donor sperm coinciding with days 11 and 13 of an ideal, 28-day cycle. From 3 days after the second insemination until the onset of menses or until pregnancy was confirmed by ultrasound, they were given an intramuscular injection three times a week (Monday, Wednesday, and Friday) from numbered but otherwise unlabelled vials containing, at random, either hCG(APL, Ayerst; 1000 IU per injection) or physiological saline randomly distributed with a random number table. We have completed 74 study cycles during which 15 pregnancies were achieved. In 35 saline-treated cycles 3 pregnancies occurred (a recognisable fecundability rate of 0 - 09), while in 39 hCG-treated cycles 12 pregnancies occurred (a rate of 0 -. 31) (x2 5 -37, p = 0 -02; Cochran’s modification ofx=4-33, p<0 05). In the 27 cycles in which hCG was administered but pregnancy did not occur, the luteal phase was prolonged by a mean±SEM of 4 -4±0 - 7 days in 11 cycles, but menses were not delayed in 16 cycles. There were 2 spontaneous abortions in the hCG-treated group. It is unclear why recognisable fecundability in the control group is slightly lower than that generally reported for women receiving AID (0-12-018507) but the randomised study design makes the increase m pregnancies in the hCG-treated group all the more striking in =
comparison. It is conceivable that, under normal conditions, hCG production by the early blastocyst that is sufficient to rescue the corpus luteum could occasionally be delayed, resulting in the onset of menses and loss of the pregnancy before recognition. Our findings suggest that it may be possible to increase the rate of implantation by supporting the corpus luteum with exogenous hCG until the implanting blastocyst can subserve this function independently. Alternatively,8 endometrial changes which result from progesterone elevation8 may favour implantation, and we also need to explore the effects of exogenous progesterone administration during the luteal phase on 1 London H. Human fertility: the basic components Chicago University of Chicago Press, 1977. 2 Trounson AO, Mohr LR, Wood C, Leeton JF. Effect of delayed insemination on invitro fertilization, culture and transfer of human embryos.J Reprod Fertil 1982; 64: 285-94 3 Bongaarts J A method for the estimation of fecundability. Demography 1975; 12: 645-60 4 Lenton EA, Sulaiman R, Sobowale O, Cooke ID. The human menstrual cycle: plasma concentrations of prolactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. J Reprod Fertil 1982, 65: 131-39 5 Katzorke T, Propping D, Tauber PF. Results of donor artificial insemination(AID)in 415 couples. Int J Fertil 1981; 26: 260-66 6 Albrecht BH, Cramer D, Schiff I. Factors influencing the success of artificial insemination. Fertill Steril 1982; 37: 792-97. 7 Hanson FW, Overstreet JW, Katz DJ. A study of the relationship of motile sperm numbers in cervical mucus 48 hours after artificial insemination with subsequent fertility. AmJ Obstet Gynecol 1982; 143: 85-90. 8. Kreitman-Gimbal B, Bayard F, Hodgen GD. Changing ratios of nuclear estrone to estradiol binding in endometrium at implantation. Regulation by chorionic gonadotropin and progesterone during rescue of the primate corpus luteum. J Clin Endocrinol Metab 1981; 52: 133-37.
recognisable fecundability. In either case, since onset of menses was delayed in less than half of the hCG-treated cycles not resulting in pregnancy, the dosage of hCG used in this study may have been borderline, and a larger dose which consistently prolongs luteal function may be associated with still higher pregnancy rates. In view of the emotional (and financial) impact of the repeated attempts at artificial insemination and in vitro fertilisation required to achieve a pregnancy, a method that enhances fecundability could prove important. Our results may also have potential value in the treatment of "idiopathic" infertility in apparently normal couples. This work
was
supported by the
Medical Research Council of Canada.
Departments of Obstetrics and Gynaecology and Biophysics and Physiology, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 1W3
Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario
ROBERT F. CASPER ELAINE WILSON JOHN A. COLLINS
STANLEY E. BROWN PARKER
JANE ANN
STAPHYLOCOCCUS EPIDERMIDIS INFECTIONS IN ACUTE MYELOBLASTIC LEUKAEMIA PATIENTS FITTED WITH HICKMAN CATHETERS
SIR,-An increased incidence of Staphylococcus epidermidis infections in granulocytopenic patients has been described in reportsl°2 from Los Angeles and Baltimore. The emergence of this usually non-pathogenic microorganism as a cause of infection in been to has related immunocompromised patients and the use of Hickman catheters. However, granulocytopenia there is disagreement about the role of long-term indwelling catheters to explain the recent increase in the incidence of infections caused by S epidermidis. Our experience may help to clarify this issue. Between September, 1982, and September, 1983, we implanted 34 Hickman catheters to 34 patients with acute myeloblastic leukaemia (AML) admitted for intensive chemotherapy3(28 for induction remission at diagnosis, 5 in relapse, and 1 for late intensification in remission). Sixty episodes of granulocytopenia were recorded in patients while the catheters were in place. Oral antibiotics or other preventive techniques (eg, granulocyte transfusions and laminar air flow rooms) were not used. The daily care of the catheter was provided by the patient’s primary nurse, following Hickman and colleagues’ guidelines.Empirical broad-spectrum antibiotics therapy with carbenicillin plus amikacin was given to all granulocytopenic patients in whom fever developed. Vancomycin was added when a S epidermidis infection was diagnosed or strongly
suspected (exit site or tunnel infection). Forty-nine microorganisms were isolated in thirty episodes of bacteraemia in 23 patients with chemotherapy associated granulocytopenia. The commonest was S epidermidis (alone in twelve and in association with other organisms in six episodes). S epidermidis bacteraemia was considered clinically significant in only nine of these eighteen episodes. Exit site infections were observed eight times in 8 patients, but only five were bacteriologically confirmed (2 S epidermidis, 2 S epidermidis plus Corynebacterium spp, and 1 P aeruginosa). 7 out of these 8 patients acquired bacteraemia. In 4 patients the same microorganism was grown from both sites (2 Sepidermidis, 1 Corynebacterium spp, and 1 P aeruginosa). 1. Winston
DJ, Dudnick DV, Chapin M, Ho WG, Gale RP, Martin WJ. Coagulasenegative staphylococcal bacteremia in patients receiving immunosuppresive therapy. Arch Intern Med 1983; 143: 32-36. 2. Wade JC, Schimpff SC, Newman K, Wiernick PH. Staphylococcus epidermidis an increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982; 97: 503-08 3. Sanz M, Gonzalez M, Besalduch J, Martinez J, Rafecas J, Martin G, Marty ML Prolonged remission maintenance in ANLL with intensive sequential combination chemotherapy. 3rd International Symposium on Therapy of Acute Leukemias. (Rome, 1982): abstr 365 4. Hickman RO, Buckner D, Clift RA, Sanders JE, Stewart P, Thomas ED. A modified right atrial catheter for access to the venous system in marrow transplant recipients. Surg Gynecol Obstet 1979; 148: 871-75
SIR,-The efficiency of human fertilisation, both natural’ and in about 85%. However, the probability of conception,
vitro,2 is
recognisable by the absence of menses (recognisable fecundability rate), is only 0 -20-0’25 for women under the age of 30.1°3 This difference suggests that implantation of the fertilised ovum is the rate-limiting step in human fertility. An observation by Lenton et al,4 that serum progesterone levels during days 3-8 of the luteal phase were higher in conception cycles than in non-conception cycles, led us to investigate the possibility of enhancing implantation and recognisable fecundability by stimulating corpus luteum function with exogenous human chorionic gonadotropin
(hCG). Women with primary infertility who were receiving artificial insemination with donor sperm (AID) because their husbands were azoospermic or severely oligospermic volunteered for this study. We chose these women because ovulation and tubal patency had been proven and we could control the timing of insemination. A randomised, double-blind controlled study was done at two university centres with established artificial insemination programmes. Most patients received two inseminations with fresh donor sperm coinciding with days 11 and 13 of an ideal, 28-day cycle. From 3 days after the second insemination until the onset of menses or until pregnancy was confirmed by ultrasound, they were given an intramuscular injection three times a week (Monday, Wednesday, and Friday) from numbered but otherwise unlabelled vials containing, at random, either hCG(APL, Ayerst; 1000 IU per injection) or physiological saline randomly distributed with a random number table. We have completed 74 study cycles during which 15 pregnancies were achieved. In 35 saline-treated cycles 3 pregnancies occurred (a recognisable fecundability rate of 0 - 09), while in 39 hCG-treated cycles 12 pregnancies occurred (a rate of 0 -. 31) (x2 5 -37, p = 0 -02; Cochran’s modification ofx=4-33, p<0 05). In the 27 cycles in which hCG was administered but pregnancy did not occur, the luteal phase was prolonged by a mean±SEM of 4 -4±0 - 7 days in 11 cycles, but menses were not delayed in 16 cycles. There were 2 spontaneous abortions in the hCG-treated group. It is unclear why recognisable fecundability in the control group is slightly lower than that generally reported for women receiving AID (0-12-018507) but the randomised study design makes the increase m pregnancies in the hCG-treated group all the more striking in =
comparison. It is conceivable that, under normal conditions, hCG production by the early blastocyst that is sufficient to rescue the corpus luteum could occasionally be delayed, resulting in the onset of menses and loss of the pregnancy before recognition. Our findings suggest that it may be possible to increase the rate of implantation by supporting the corpus luteum with exogenous hCG until the implanting blastocyst can subserve this function independently. Alternatively,8 endometrial changes which result from progesterone elevation8 may favour implantation, and we also need to explore the effects of exogenous progesterone administration during the luteal phase on 1 London H. Human fertility: the basic components Chicago University of Chicago Press, 1977. 2 Trounson AO, Mohr LR, Wood C, Leeton JF. Effect of delayed insemination on invitro fertilization, culture and transfer of human embryos.J Reprod Fertil 1982; 64: 285-94 3 Bongaarts J A method for the estimation of fecundability. Demography 1975; 12: 645-60 4 Lenton EA, Sulaiman R, Sobowale O, Cooke ID. The human menstrual cycle: plasma concentrations of prolactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. J Reprod Fertil 1982, 65: 131-39 5 Katzorke T, Propping D, Tauber PF. Results of donor artificial insemination(AID)in 415 couples. Int J Fertil 1981; 26: 260-66 6 Albrecht BH, Cramer D, Schiff I. Factors influencing the success of artificial insemination. Fertill Steril 1982; 37: 792-97. 7 Hanson FW, Overstreet JW, Katz DJ. A study of the relationship of motile sperm numbers in cervical mucus 48 hours after artificial insemination with subsequent fertility. AmJ Obstet Gynecol 1982; 143: 85-90. 8. Kreitman-Gimbal B, Bayard F, Hodgen GD. Changing ratios of nuclear estrone to estradiol binding in endometrium at implantation. Regulation by chorionic gonadotropin and progesterone during rescue of the primate corpus luteum. J Clin Endocrinol Metab 1981; 52: 133-37.
recognisable fecundability. In either case, since onset of menses was delayed in less than half of the hCG-treated cycles not resulting in pregnancy, the dosage of hCG used in this study may have been borderline, and a larger dose which consistently prolongs luteal function may be associated with still higher pregnancy rates. In view of the emotional (and financial) impact of the repeated attempts at artificial insemination and in vitro fertilisation required to achieve a pregnancy, a method that enhances fecundability could prove important. Our results may also have potential value in the treatment of "idiopathic" infertility in apparently normal couples. This work
was
supported by the
Medical Research Council of Canada.
Departments of Obstetrics and Gynaecology and Biophysics and Physiology, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 1W3
Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario
ROBERT F. CASPER ELAINE WILSON JOHN A. COLLINS
STANLEY E. BROWN PARKER
JANE ANN
STAPHYLOCOCCUS EPIDERMIDIS INFECTIONS IN ACUTE MYELOBLASTIC LEUKAEMIA PATIENTS FITTED WITH HICKMAN CATHETERS
SIR,-An increased incidence of Staphylococcus epidermidis infections in granulocytopenic patients has been described in reportsl°2 from Los Angeles and Baltimore. The emergence of this usually non-pathogenic microorganism as a cause of infection in been to has related immunocompromised patients and the use of Hickman catheters. However, granulocytopenia there is disagreement about the role of long-term indwelling catheters to explain the recent increase in the incidence of infections caused by S epidermidis. Our experience may help to clarify this issue. Between September, 1982, and September, 1983, we implanted 34 Hickman catheters to 34 patients with acute myeloblastic leukaemia (AML) admitted for intensive chemotherapy3(28 for induction remission at diagnosis, 5 in relapse, and 1 for late intensification in remission). Sixty episodes of granulocytopenia were recorded in patients while the catheters were in place. Oral antibiotics or other preventive techniques (eg, granulocyte transfusions and laminar air flow rooms) were not used. The daily care of the catheter was provided by the patient’s primary nurse, following Hickman and colleagues’ guidelines.Empirical broad-spectrum antibiotics therapy with carbenicillin plus amikacin was given to all granulocytopenic patients in whom fever developed. Vancomycin was added when a S epidermidis infection was diagnosed or strongly
suspected (exit site or tunnel infection). Forty-nine microorganisms were isolated in thirty episodes of bacteraemia in 23 patients with chemotherapy associated granulocytopenia. The commonest was S epidermidis (alone in twelve and in association with other organisms in six episodes). S epidermidis bacteraemia was considered clinically significant in only nine of these eighteen episodes. Exit site infections were observed eight times in 8 patients, but only five were bacteriologically confirmed (2 S epidermidis, 2 S epidermidis plus Corynebacterium spp, and 1 P aeruginosa). 7 out of these 8 patients acquired bacteraemia. In 4 patients the same microorganism was grown from both sites (2 Sepidermidis, 1 Corynebacterium spp, and 1 P aeruginosa). 1. Winston
DJ, Dudnick DV, Chapin M, Ho WG, Gale RP, Martin WJ. Coagulasenegative staphylococcal bacteremia in patients receiving immunosuppresive therapy. Arch Intern Med 1983; 143: 32-36. 2. Wade JC, Schimpff SC, Newman K, Wiernick PH. Staphylococcus epidermidis an increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982; 97: 503-08 3. Sanz M, Gonzalez M, Besalduch J, Martinez J, Rafecas J, Martin G, Marty ML Prolonged remission maintenance in ANLL with intensive sequential combination chemotherapy. 3rd International Symposium on Therapy of Acute Leukemias. (Rome, 1982): abstr 365 4. Hickman RO, Buckner D, Clift RA, Sanders JE, Stewart P, Thomas ED. A modified right atrial catheter for access to the venous system in marrow transplant recipients. Surg Gynecol Obstet 1979; 148: 871-75