Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1973 May;52(5):1122–1128. doi: 10.1172/JCI107278

Suppression of Urinary and Plasma Follicle-Stimulating Hormone by Exogenous Estrogens in Prepubertal and Pubertal Children

R P Kelch 1, S L Kaplan 1, M M Grumbach 1
PMCID: PMC302367  PMID: 4700487

Abstract

Clomiphene citrate, an “anti-estrogen” with mild estrogenic properties, inhibits rather than stimulates gonadotropin excretion in prepubertal and early pubertal children. These and other data suggest that the sensitivity of the hypothalamic-pituitary “gonadostat” decreases at the onset of puberty. To test this hypothesis further, the daily excretion of urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) was determined in 19 children (5 “short normals” and 14 with isolated human growth hormone (HGH) deficiency) who were given ethinyl estradiol (EE) 1.4-14.7 μg/m2 per day (2-10 μg/day) for 4 to 7 days. In addition, plasma and urinary gonadotropins and plasma estrogens were serially determined in two prepubertal females(with isolated HGH deficiency) given two injections (24 h apart) of estradiol benzoate, 10 μg/kg. FSH and LH concentrations in plasma and kaolin-acetone urinary concentrates and plasma 17β-estradiol (E2) and estrone (E1) were measured by radioimmunoassays. 2-3 μg/m2 per day of EE significantly suppressed urinary FSH (and LH when detected in the control period) in two out of six prepubertal children, while all doses >5 μg/m2 per day suppressed urinary gonadotropins to undetectable levels in eight prepubertal subjects. In early to midpubertal subjects. 2-10 μg/m2 per day of EE produced a slight suppression of urinary FSH, but failed to suppress to undetectable levels. Two subjects in late puberty (stage 4) did not suppress their urinary FSH while on 7 and 8.3 μg/m2 per day. In both subjects treated with estradiol benzoate, plasma FSH promptly decreased after the first injection. Urinary FSH was suppressed to <0.1 IU/day on day 2 and urinary and plasma gonadotropins remained suppressed for the duration of the study (3 days). Plasma E2 and E1 rose from prepubertal values to peak concentrations of 150 to 250 pg/ml (E2), and 50 and 100 pg/ml (E1) at approximately 36 h. We conclude that the hypothalamic-pituitary-gonadal axis is operative in the prepubertal child and that the sensitivity of the hypothalamic-pituitary center(s) which control the secretion of FSH and LH decreases at the onset of puberty in man.

Full text

PDF
1122

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALBERT A. Human urinary gonadotropin. Recent Prog Horm Res. 1956;12:227-96; discussion, 296-301. [PubMed] [Google Scholar]
  2. August G. P., Grumbach M. M., Kaplan S. L. Hormonal changes in puberty. 3. Correlation of plasma testosterone, LH, FSH, testicular size, and bone age with male pubertal development. J Clin Endocrinol Metab. 1972 Feb;34(2):319–326. doi: 10.1210/jcem-34-2-319. [DOI] [PubMed] [Google Scholar]
  3. Bardin C. W., Ross G. T., Lipsett M. B. Site of action of clomiphene citrate in men: a study of the pituitary-Leydig cell axis. J Clin Endocrinol Metab. 1967 Nov;27(11):1558–1564. doi: 10.1210/jcem-27-11-1558. [DOI] [PubMed] [Google Scholar]
  4. Burr I. M., Sizonenko P. C., Kaplan S. L., Grumbach M. M. Hormonal changes in puberty. I. Correlation of serum luteinizing hormone and follicle stimulating hormone with stages of puberty, testicular size, and bone age in normal boys. Pediatr Res. 1970 Jan;4(1):25–35. doi: 10.1203/00006450-197001000-00003. [DOI] [PubMed] [Google Scholar]
  5. Cathro D. M., Saez J. M., Bertrand J. The effect of clomiphene on the plasma androgens of prepubertal and pubertal boys. J Endocrinol. 1971 Jul;50(3):387–396. doi: 10.1677/joe.0.0500387. [DOI] [PubMed] [Google Scholar]
  6. FITSCHEN W., CLAYTON B. E. URINARY EXCRETION OF GONADOTROPHINS WITH PARTICULAR REFERENCE TO CHILDREN. Arch Dis Child. 1965 Feb;40:16–26. doi: 10.1136/adc.40.209.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Faiman C., Winter J. S. Sex differences in gonadotrophin concentrations in infancy. Nature. 1971 Jul 9;232(5306):130–131. doi: 10.1038/232130a0. [DOI] [PubMed] [Google Scholar]
  8. Goodman H. G., Grumbach M. M., Kaplan S. L. Growth and growth hormone. II. A comparison of isolated growth-hormone deficiency and multiple pituitary-hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med. 1968 Jan 11;278(2):57–68. doi: 10.1056/NEJM196801112780201. [DOI] [PubMed] [Google Scholar]
  9. Jenner M. R., Kelch R. P., Kaplan S. L., Grümbach M. M. Hormonal changes in puberty. IV. Plasma estradiol, LH, and FSH in prepubertal children, pubertal females, and in precocious puberty, premature thelarche, hypogonadism, and in a child with a feminizing ovarian tumor. J Clin Endocrinol Metab. 1972 Mar;34(3):521–530. doi: 10.1210/jcem-34-3-521. [DOI] [PubMed] [Google Scholar]
  10. Kelch R. P., Jenner M. R., Weinstein R., Kaplan S. L., Grumbach M. M. Estradiol and testosterone secretion by human, simian, and canine testes, in males with hypogonadism and in male pseudohermaphrodites with the feminizing testes syndrome. J Clin Invest. 1972 Apr;51(4):824–830. doi: 10.1172/JCI106877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kulin H. E., Grumbach M. M., Kaplan S. L. Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man. Science. 1969 Nov 21;166(3908):1012–1013. doi: 10.1126/science.166.3908.1012. [DOI] [PubMed] [Google Scholar]
  12. Kulin H. E., Grumbach M. M., Kaplan S. L. Gonadal-hypothalamic interaction in prepubertal and pubertal man: effect of clomiphene citrate on urinary follicle-stimulating hormone and luteinizing hormone and plasma testosterone. Pediatr Res. 1972 Mar;6(3):162–171. doi: 10.1203/00006450-197203000-00004. [DOI] [PubMed] [Google Scholar]
  13. Laron Z., Zilka E. Compensatory hypertrophy of testicle in unilateral cryptorchidism. J Clin Endocrinol Metab. 1969 Nov;29(11):1409–1413. doi: 10.1210/jcem-29-11-1409. [DOI] [PubMed] [Google Scholar]
  14. Mikhail G., Wu C. H., Ferin M., Vande Wiele R. L. Radioimmunoassay of plasma estrone and estradiol. Steroids. 1970 Mar;15(3):333–352. doi: 10.1016/s0039-128x(70)80053-8. [DOI] [PubMed] [Google Scholar]
  15. Penny R., Guyda H. J., Baghdassarian A., Johanson A. J., Blizzard R. M. Correlation of serum follicular stimulating hormone (FSH) and luteinizing hormone (LH) as measured by radioimmunoassay in disorders of sexual development. J Clin Invest. 1970 Oct;49(10):1847–1852. doi: 10.1172/JCI106402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Peterson N. T., Jr, Midgley A. R., Jr, Jaffe R. B. Regulation of human gonadotropins. 3. Luteinizing hormone and follicle stimulating hormone in sera from adult males. J Clin Endocrinol Metab. 1968 Oct;28(10):1473–1478. doi: 10.1210/jcem-28-10-1473. [DOI] [PubMed] [Google Scholar]
  17. RAMIREZ D. V., McCANN S. M. Comparison of the regulation of luteinizing hormone (LH) secretion in immature and adult rats. Endocrinology. 1963 Mar;72:452–464. doi: 10.1210/endo-72-3-452. [DOI] [PubMed] [Google Scholar]
  18. ROY S., GREENBLATT R. B., MAHESH V. B., JUNGCK E. C. CLOMIPHENE CITRATE: FURTHER OBSERVATIONS ON ITS USE IN INDUCTION OF OVULATION IN THE HUMAN AND ON ITS MODE OF ACTION. Fertil Steril. 1963 Nov-Dec;14:575–595. doi: 10.1016/s0015-0282(16)35041-5. [DOI] [PubMed] [Google Scholar]
  19. Rifkind A. B., Kulin H. E., Rayford P. L., Cargille C. M., Ross G. T. 24-Hour urinary luteinizing hormone (LW) and follicle stimulating hormone (FSH) excretion in normal children. J Clin Endocrinol Metab. 1970 Nov;31(5):517–525. doi: 10.1210/jcem-31-5-517. [DOI] [PubMed] [Google Scholar]
  20. Rifkind A. B., Kulin H. E., Ross G. T. Follicle-stimulating hormone (FSH) and luteninizing hormone (LH) in the urine of prepubertal children. J Clin Invest. 1967 Dec;46(12):1925–1931. doi: 10.1172/JCI105682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Roth J. C., Kelch R. P., Kaplan S. L., Grumbach M. M. FSH and LH response to luteinizing hormone-releasing factor in prepubertal and pubertal children, adult males and patients with hypogonadotropic and hypertropic hypogonadism. J Clin Endocrinol Metab. 1972 Dec;35(6):926–930. doi: 10.1210/jcem-35-6-926. [DOI] [PubMed] [Google Scholar]
  22. Santen R. J., Leonard J. M., Sherins R. J., Gandy H. M., Paulsen C. A. Short- and long-term effects of clomiphene citrate on the pituitary-testicular axis. J Clin Endocrinol Metab. 1971 Dec;33(6):970–979. doi: 10.1210/jcem-33-6-970. [DOI] [PubMed] [Google Scholar]
  23. Sizonenko P. C., Burr I. M., Kaplan S. L., Grumbach M. M. Hormonal changes in puberty. II. Correlation of serum luteinizing hormone and follicle stimulating hormone with stages of puberty and bone age in normal girls. Pediatr Res. 1970 Jan;4(1):36–45. doi: 10.1203/00006450-197001000-00004. [DOI] [PubMed] [Google Scholar]
  24. Smith E. R., Davidson J. M. Differential responses to hypothalamic testosterone in relation to male puberty. Am J Physiol. 1967 Jun;212(6):1385–1390. doi: 10.1152/ajplegacy.1967.212.6.1385. [DOI] [PubMed] [Google Scholar]
  25. Smith E. R., Davidson J. M. Role of estrogen in the cerebral control of puberty in female rats. Endocrinology. 1968 Jan;82(1):100–108. doi: 10.1210/endo-82-1-100. [DOI] [PubMed] [Google Scholar]
  26. Wood J. R., Wrenn T. R., Bitman J. Estrogenic and antiestrogenic effects of clomiphene, MER-25 and CN-55,945-27 on the rat uterus and vagina. Endocrinology. 1968 Jan;82(1):69–74. doi: 10.1210/endo-82-1-69. [DOI] [PubMed] [Google Scholar]
  27. Wu C. H., Lundy L. E. Radioimmunoassay of plasma estrogens. Steroids. 1971 Jul;18(1):91–111. doi: 10.1016/s0039-128x(71)80174-5. [DOI] [PubMed] [Google Scholar]
  28. Yen S. S., Tsai C. C. The biphasic pattern in the feedback action of ethinyl estradiol on the release of pituitary FSH and LH. J Clin Endocrinol Metab. 1971 Dec;33(6):882–887. doi: 10.1210/jcem-33-6-882. [DOI] [PubMed] [Google Scholar]
  29. Youlton R., Kaplan S. L., Grumbach M. M. Growth and growth hormone. IV. Limitations of the growth hormone response to insulin and arginine and of the immunoreactive insulin response to arginine in the assessment of growth hormone deficiency in children. Pediatrics. 1969 Jun;43(6):989–1004. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES