747
IMPAIRED HYPOTHALAMIC CONTROL OF PROLACTIN SECRETION IN MASSIVE OBESITY P. G. KOPELMAN T. R. E. PILKINGTON
N. WHITE L. S. JEFFCOATE
Department of Medicine, St. George’s Hospital and Medical School, and Department of Endocrinology, Chelsea Hospital for Women, London Intravenous insulin tolerance tests and
Summary
thyrotropin-releasing hormone (T.R.H.) stimulation tests were performed in nine massively obese women and six lean female controls and the prolactin, growth hormone, and cortisol responses were measured. A combined pituitary function test (insulin, T.R.H., and gonadotropin-releasing hormone) was performed in eleven other massively obese women. In the obese women to whom insulin was given separately there was no prolactin release, and growth hormone and cortisol responses were impaired. T.R.H. stimulation produced a prolactin response which was subnormal. These changes were not apparent in the obese women in whom a combined pituitary function test was performed. The results suggest an alteration of hypothalamic function in massive obesity.
Introduction A DISORDER of hypothalamic function is suspected in human obesity but the impaired growth-hormone response to insulin-induced hypoglycxmia is the only evidence for this.l,2 We attempted to obtain further inforDR SHAPIRO AND OTHERS: REFERENCES
1. Jordan, W. M. Lancet, 1961, ii, 1146. 2. Vessey, M. P. in Risks, Benefits and Controversies in Fertility Control edited by J. J. Sciarra, G. I. Zatuchni and J. J. Speidel); p. 113. Hagerstown, Maryland 1978. 3. Stolley, P. D. ibid. p. 122. 4. Dugdale, M., Masi, A. T. Effects of the Oral Contraceptive on Blood Clotting, Second report on the Oral Contraceptive Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration; p. 43, Washington, D.C., Government Printing Office, 1969. 5 Dugdale, M., Masi, A. T. J. chron. Dis. 1971, 23, 775 6 Inman, W.H.W., Vessey, M. P. Br. med. J. 1968, ii, 193. 7 Vessey, M. P., Doll, R. ibid. 1969, ii, 651. 8 Inman, W. H. W., Vessey, M. P., Westerholm, B., Egelund, A. ibid. 1970, ii, 203. 9. Fischer, A. J., Mosbech, J. Ugeskr Laeger, 1970, 132, 2480. 10 11 12 13 14 15 16 17
about hypothalamo-pituitary function in massively obese patients by studying prolactin release. Prolactin release in people of normal weight is stimulated by insulin-induced hypoglycxmia3 and by intravenous thyrotropin-releasing hormone (T.R.H.), which acts directly on pituitary cells.’ We therefore performed, either separately or in combination, intravenous insulin tolerance and T.R.H. stimulation tests in obese patients, and compared the prolactin, growth hormone, and cortisol responses observed with those seen in lean controls.
mation
Oliver, M. F. Br. med J. 1970, ii, 210.
Radford, D. J., Oliver, M. F. ibid. 1973, iii, 428. Oliver, M. F. ibid. 1974, iv, 253. Mann, J. I., Inman, W. H. W. ibid. 1975, ii, 245. Mann, J. I., Vessey, M. P., Thorogood, M., Doll, R. ibid. 1975, ii, 241. Mann, J I., Thorogood, M., Waters, W. E., Powell, C. ibid. 1975, iii, 631. Mann, J. I., Inman, W. H. W., Thorogood, M. ibid. 1976, ii, 445. Mann, J. I., Doll, R., Thorogood, M., Vessey, M. P., Waters, W. E. Br. J. prev soc. Med. 1976, 30, 94. 18 Jain, A. K. Am.J. Obstet Gynec. 1976, 126, 301. 19 Ory, H W. J. Am. med. Ass. 1977, 237, 2619. 20 Royal College of General Practitioners’ Oral Contraception Study, Lancet,
1977, ii, 727.
21. Slone, D., Shapiro, S., Rosenberg, L., Kaufman, D. W., Hartz, S. C., Rossi, A. C, Stolley, P. D., Miettinen, O. S. New Engl. J. Med. 1978, 298, 1273. 22 Ischæmic Heart Disease Registers: Report of the Fifth Working Group, Copenhagen, World Health Organisation, 1971.
23 Truett, J., Cornfield, J., Kannel, W. A. J. chron. Dis. 1967, 20, 511. 24 Mantel, N, Haenszel, W. J. natn. Cancer Inst. 1959, 22, 719. 25 Miettinen, O. S. Am. J. Epidem. 1976, 103, 226. 26 Glass, R, Johnson, B., Vessey, M. P. Br. J. prev. soc. Med. 1974, 28, 273. 27 Stolley, P. D., Tonascia, J. A., Tockman, M. S., Sartwell, P. E., Rutledge, A H, Jacobs, M P Am. J. Epidem. 1975, 102, 197. 28 Laragh, H. Am. J. Obstet. Gynec. 1971, 109, 210. 29
Stokes, T, Wynn, V. Lancet, 1971, ii, 677. 30 bek H., B., Rothman, K. J. J. Am. med. Ass. 1978, 239, 1403. 31 Lck H, Dinan, B., Herman, R., Rothman, K. J. ibid. 1978, 240, 2548.
Dinan,
Patients and Methods The following subjects were studied: nine obese women (mean 240 % ideal body-weight [i.s.w.], range 200-290 %; mean age 33, range 26-49) in whom an intravenous insulin tolerance test (0-15 units/kg soluble insulin) and an intravenous T.R.H. stimulation test (200 µg) were performed on different occasions, and in random order; six female volunteers (mean weight 100 % I.B.w., range 90-105 %; mean age 24, range 19-28) who also had an insulin tolerance test (0-1 units/kg soluble insulin) and T.R.H. test (200 fLg) on separate occasions; eleven obese women (mean weight 220 % I.B.W., range 180-270 %; mean age 34, range 17-56) to whom a combined injection of soluble insulin (0-15 units/kg), T.R.H. (200 µg), and gonadotropin-releasing hormone (100 ug) was given. I.B.W. was defined as the midpoint of the weight range for medium frame size as listed by the Metropolitan Life Insurance Company Table. Obese subjects were studied in hospital on a weight-maintaining diet and informed consent was obtained for the investigations. None was taking any medication. Each test was performed in the morning after an overnight fast and subjects rested for at least 30 min after the insertion of an intravenous cannula, through which the blood-samples were drawn. Blood was taken at 30 min intervals for 2 h after insulin and for 1 h after T.R.H. Blood-glucose fell to less than 40% of the fasting level after insulin and this fall was accompanied by symptoms in all the subjects. Each sample was immediately centrifuged and the plasma was frozen and stored at -20 ° C until assay. Growth hormone, prolactin, and cortisol were measured by specific radioimmunoassays (R.I.A.). The standard used in the growth hormone R.I.A. was I.R.P. 66/217, and the prolactin standard was I.R.P. 75/504.
weight
Results All values are given in relation to basal values (100 %), and are mean maximum increments + standard error of the mean (s.E.M.). The Student’st test of statistical significance was used for all significance calculations. Basal Hormone Concentrations Mean + S.E.M. concentrations of hormones in the basal samples from the twenty obese subjects were prolactin 370 + 60 mi.u./l, growth hormone 2.4+_05 mi.u./l, and cortisol 506:t34 nmol/1. In the six lean controls basal concentrations were prolactin 330+_60 mi.u./l, growth hormone 3.2±0.5 mi.u./l, and cortisol 325+ 59 nmol/1. Prolactin and growth hormone results were not significantly different in the two groups, but in the the basal plasma-cortisol was higher (n
IMPAIRED HYPOTHALAMIC CONTROL OF PROLACTIN SECRETION IN MASSIVE OBESITY P. G. KOPELMAN T. R. E. PILKINGTON
N. WHITE L. S. JEFFCOATE
Department of Medicine, St. George’s Hospital and Medical School, and Department of Endocrinology, Chelsea Hospital for Women, London Intravenous insulin tolerance tests and
Summary
thyrotropin-releasing hormone (T.R.H.) stimulation tests were performed in nine massively obese women and six lean female controls and the prolactin, growth hormone, and cortisol responses were measured. A combined pituitary function test (insulin, T.R.H., and gonadotropin-releasing hormone) was performed in eleven other massively obese women. In the obese women to whom insulin was given separately there was no prolactin release, and growth hormone and cortisol responses were impaired. T.R.H. stimulation produced a prolactin response which was subnormal. These changes were not apparent in the obese women in whom a combined pituitary function test was performed. The results suggest an alteration of hypothalamic function in massive obesity.
Introduction A DISORDER of hypothalamic function is suspected in human obesity but the impaired growth-hormone response to insulin-induced hypoglycxmia is the only evidence for this.l,2 We attempted to obtain further inforDR SHAPIRO AND OTHERS: REFERENCES
1. Jordan, W. M. Lancet, 1961, ii, 1146. 2. Vessey, M. P. in Risks, Benefits and Controversies in Fertility Control edited by J. J. Sciarra, G. I. Zatuchni and J. J. Speidel); p. 113. Hagerstown, Maryland 1978. 3. Stolley, P. D. ibid. p. 122. 4. Dugdale, M., Masi, A. T. Effects of the Oral Contraceptive on Blood Clotting, Second report on the Oral Contraceptive Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration; p. 43, Washington, D.C., Government Printing Office, 1969. 5 Dugdale, M., Masi, A. T. J. chron. Dis. 1971, 23, 775 6 Inman, W.H.W., Vessey, M. P. Br. med. J. 1968, ii, 193. 7 Vessey, M. P., Doll, R. ibid. 1969, ii, 651. 8 Inman, W. H. W., Vessey, M. P., Westerholm, B., Egelund, A. ibid. 1970, ii, 203. 9. Fischer, A. J., Mosbech, J. Ugeskr Laeger, 1970, 132, 2480. 10 11 12 13 14 15 16 17
about hypothalamo-pituitary function in massively obese patients by studying prolactin release. Prolactin release in people of normal weight is stimulated by insulin-induced hypoglycxmia3 and by intravenous thyrotropin-releasing hormone (T.R.H.), which acts directly on pituitary cells.’ We therefore performed, either separately or in combination, intravenous insulin tolerance and T.R.H. stimulation tests in obese patients, and compared the prolactin, growth hormone, and cortisol responses observed with those seen in lean controls.
mation
Oliver, M. F. Br. med J. 1970, ii, 210.
Radford, D. J., Oliver, M. F. ibid. 1973, iii, 428. Oliver, M. F. ibid. 1974, iv, 253. Mann, J. I., Inman, W. H. W. ibid. 1975, ii, 245. Mann, J. I., Vessey, M. P., Thorogood, M., Doll, R. ibid. 1975, ii, 241. Mann, J I., Thorogood, M., Waters, W. E., Powell, C. ibid. 1975, iii, 631. Mann, J. I., Inman, W. H. W., Thorogood, M. ibid. 1976, ii, 445. Mann, J. I., Doll, R., Thorogood, M., Vessey, M. P., Waters, W. E. Br. J. prev soc. Med. 1976, 30, 94. 18 Jain, A. K. Am.J. Obstet Gynec. 1976, 126, 301. 19 Ory, H W. J. Am. med. Ass. 1977, 237, 2619. 20 Royal College of General Practitioners’ Oral Contraception Study, Lancet,
1977, ii, 727.
21. Slone, D., Shapiro, S., Rosenberg, L., Kaufman, D. W., Hartz, S. C., Rossi, A. C, Stolley, P. D., Miettinen, O. S. New Engl. J. Med. 1978, 298, 1273. 22 Ischæmic Heart Disease Registers: Report of the Fifth Working Group, Copenhagen, World Health Organisation, 1971.
23 Truett, J., Cornfield, J., Kannel, W. A. J. chron. Dis. 1967, 20, 511. 24 Mantel, N, Haenszel, W. J. natn. Cancer Inst. 1959, 22, 719. 25 Miettinen, O. S. Am. J. Epidem. 1976, 103, 226. 26 Glass, R, Johnson, B., Vessey, M. P. Br. J. prev. soc. Med. 1974, 28, 273. 27 Stolley, P. D., Tonascia, J. A., Tockman, M. S., Sartwell, P. E., Rutledge, A H, Jacobs, M P Am. J. Epidem. 1975, 102, 197. 28 Laragh, H. Am. J. Obstet. Gynec. 1971, 109, 210. 29
Stokes, T, Wynn, V. Lancet, 1971, ii, 677. 30 bek H., B., Rothman, K. J. J. Am. med. Ass. 1978, 239, 1403. 31 Lck H, Dinan, B., Herman, R., Rothman, K. J. ibid. 1978, 240, 2548.
Dinan,
Patients and Methods The following subjects were studied: nine obese women (mean 240 % ideal body-weight [i.s.w.], range 200-290 %; mean age 33, range 26-49) in whom an intravenous insulin tolerance test (0-15 units/kg soluble insulin) and an intravenous T.R.H. stimulation test (200 µg) were performed on different occasions, and in random order; six female volunteers (mean weight 100 % I.B.w., range 90-105 %; mean age 24, range 19-28) who also had an insulin tolerance test (0-1 units/kg soluble insulin) and T.R.H. test (200 fLg) on separate occasions; eleven obese women (mean weight 220 % I.B.W., range 180-270 %; mean age 34, range 17-56) to whom a combined injection of soluble insulin (0-15 units/kg), T.R.H. (200 µg), and gonadotropin-releasing hormone (100 ug) was given. I.B.W. was defined as the midpoint of the weight range for medium frame size as listed by the Metropolitan Life Insurance Company Table. Obese subjects were studied in hospital on a weight-maintaining diet and informed consent was obtained for the investigations. None was taking any medication. Each test was performed in the morning after an overnight fast and subjects rested for at least 30 min after the insertion of an intravenous cannula, through which the blood-samples were drawn. Blood was taken at 30 min intervals for 2 h after insulin and for 1 h after T.R.H. Blood-glucose fell to less than 40% of the fasting level after insulin and this fall was accompanied by symptoms in all the subjects. Each sample was immediately centrifuged and the plasma was frozen and stored at -20 ° C until assay. Growth hormone, prolactin, and cortisol were measured by specific radioimmunoassays (R.I.A.). The standard used in the growth hormone R.I.A. was I.R.P. 66/217, and the prolactin standard was I.R.P. 75/504.
weight
Results All values are given in relation to basal values (100 %), and are mean maximum increments + standard error of the mean (s.E.M.). The Student’st test of statistical significance was used for all significance calculations. Basal Hormone Concentrations Mean + S.E.M. concentrations of hormones in the basal samples from the twenty obese subjects were prolactin 370 + 60 mi.u./l, growth hormone 2.4+_05 mi.u./l, and cortisol 506:t34 nmol/1. In the six lean controls basal concentrations were prolactin 330+_60 mi.u./l, growth hormone 3.2±0.5 mi.u./l, and cortisol 325+ 59 nmol/1. Prolactin and growth hormone results were not significantly different in the two groups, but in the the basal plasma-cortisol was higher (n
