Skip to main content
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2001 Mar;109(Suppl 1):21–26. doi: 10.1289/ehp.01109s121

Significant effects of mild endogenous hormonal changes in humans: considerations for low-dose testing.

F Brucker-Davis 1, K Thayer 1, T Colborn 1
PMCID: PMC1240539  PMID: 11250802

Abstract

We review the significant and adverse health effects that can occur with relatively small endogenous hormonal changes in pubertal and adult humans. We discuss the effects of hormonal changes that occur within normal physiologic ranges--such as the rising levels of estrogen in peripuberty, which cause growth spurts at low levels and then the fusion of epiphyses at higher levels--and the hormonal variations during the menstrual cycle and their relation to genital phenotypic changes and intercurrent disease evolution. We turn next to adaptive changes in gonadal and other functions during aging, exercise, stress, starvation, and chronic diseases, which can serve as models for the effects of exogenous, hormonally active compounds. Then we review the states of borderline hormonal imbalances such as subclinical (having few or very mild symptoms, if any) hypothyroidism or hyperthyroidism, glucose intolerance, and other endocrine conditions. Finally, we review the deleterious systemic effects of gonadal imbalance. Information stemming from clinical observations leads to the concept of "no threshold" within the endocrine system and thus illustrates the importance of considering low-dose testing for chemicals that interfere with hormonal activity. We also urge attention to more sensitive, less visible end points such as osteoporosis, increased risk for cardiovascular disease, or cognitive changes.

Full Text

The Full Text of this article is available as a PDF (246.4 KB).

Selected References

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

  1. Adcock C. J., Perry L. A., Lindsell D. R., Taylor A. M., Holly J. M., Jones J., Dunger D. B. Menstrual irregularities are more common in adolescents with type 1 diabetes: association with poor glycaemic control and weight gain. Diabet Med. 1994 Jun;11(5):465–470. doi: 10.1111/j.1464-5491.1994.tb00307.x. [DOI] [PubMed] [Google Scholar]
  2. Alberti K. G. The clinical implications of impaired glucose tolerance. Diabet Med. 1996 Nov;13(11):927–937. doi: 10.1002/(SICI)1096-9136(199611)13:11<927::AID-DIA279>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  3. Baker T. R., Piver M. S. Etiology, biology, and epidemiology of ovarian cancer. Semin Surg Oncol. 1994 Jul-Aug;10(4):242–248. doi: 10.1002/ssu.2980100403. [DOI] [PubMed] [Google Scholar]
  4. Bancroft J. The menstrual cycle and the well being of women. Soc Sci Med. 1995 Sep;41(6):785–791. doi: 10.1016/0277-9536(95)00045-9. [DOI] [PubMed] [Google Scholar]
  5. Barrett-Connor E., Wingard D. L., Criqui M. H., Suarez L. Is borderline fasting hyperglycemia a risk factor for cardiovascular death? J Chronic Dis. 1984;37(9-10):773–779. doi: 10.1016/0021-9681(84)90046-8. [DOI] [PubMed] [Google Scholar]
  6. Bates G. W., Garza D. E., Garza M. M. Clinical manifestations of hormonal changes in the menstrual cycle. Obstet Gynecol Clin North Am. 1990 Jun;17(2):299–310. [PubMed] [Google Scholar]
  7. Bergendahl M., Perheentupa A., Huhtaniemi I. Starvation-induced suppression of pituitary-testicular function in rats is reversed by pulsatile gonadotropin-releasing hormone substitution. Biol Reprod. 1991 Mar;44(3):413–419. doi: 10.1095/biolreprod44.3.413. [DOI] [PubMed] [Google Scholar]
  8. Biondi B., Fazio S., Carella C., Amato G., Cittadini A., Lupoli G., Saccà L., Bellastella A., Lombardi G. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab. 1993 Aug;77(2):334–338. doi: 10.1210/jcem.77.2.8345037. [DOI] [PubMed] [Google Scholar]
  9. Bonen A. Exercise-induced menstrual cycle changes. A functional, temporary adaptation to metabolic stress. Sports Med. 1994 Jun;17(6):373–392. doi: 10.2165/00007256-199417060-00004. [DOI] [PubMed] [Google Scholar]
  10. Buyalos R. P., Daneshmand S., Brzechffa P. R. Basal estradiol and follicle-stimulating hormone predict fecundity in women of advanced reproductive age undergoing ovulation induction therapy. Fertil Steril. 1997 Aug;68(2):272–277. doi: 10.1016/s0015-0282(97)81514-2. [DOI] [PubMed] [Google Scholar]
  11. Case A. M., Reid R. L. Effects of the menstrual cycle on medical disorders. Arch Intern Med. 1998 Jul 13;158(13):1405–1412. doi: 10.1001/archinte.158.13.1405. [DOI] [PubMed] [Google Scholar]
  12. Chie W. C., Hsieh C., Newcomb P. A., Longnecker M. P., Mittendorf R., Greenberg E. R., Clapp R. W., Burke K. P., Titus-Ernstoff L., Trentham-Dietz A. Age at any full-term pregnancy and breast cancer risk. Am J Epidemiol. 2000 Apr 1;151(7):715–722. doi: 10.1093/oxfordjournals.aje.a010266. [DOI] [PubMed] [Google Scholar]
  13. Chiovato L., Lapi P., Fiore E., Tonacchera M., Pinchera A. Thyroid autoimmunity and female gender. J Endocrinol Invest. 1993 May;16(5):384–391. doi: 10.1007/BF03348863. [DOI] [PubMed] [Google Scholar]
  14. Chrousos G. P., Torpy D. J., Gold P. W. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med. 1998 Aug 1;129(3):229–240. doi: 10.7326/0003-4819-129-3-199808010-00012. [DOI] [PubMed] [Google Scholar]
  15. Csermely T., Halvax L., Schmidt E., Zámbó K., Péterfai J., Vadon G., Szabó I. Alacsonyabb csontsürüség (osteopenia) raromenorrhoeás és szekunder amenorrhoeás serdülö lányok körében. Orv Hetil. 1997 Oct 26;138(43):2735–2741. [PubMed] [Google Scholar]
  16. Cutler G. B., Jr The role of estrogen in bone growth and maturation during childhood and adolescence. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):141–144. [PubMed] [Google Scholar]
  17. Danforth E., Jr, Burger A. G., Wimpfheimer C. Nutritionally-induced alterations in thyroid hormone metabolism and thermogenesis. Experientia Suppl. 1978;32:213–217. doi: 10.1007/978-3-0348-5559-4_25. [DOI] [PubMed] [Google Scholar]
  18. Fitzgerald C., Zimon A. E., Jones E. E. Aging and reproductive potential in women. Yale J Biol Med. 1998 Sep-Oct;71(5):367–381. [PMC free article] [PubMed] [Google Scholar]
  19. Franz W. B., 3rd Basic review: endocrinology of the normal menstrual cycle. Prim Care. 1988 Sep;15(3):607–616. [PubMed] [Google Scholar]
  20. Frisch R. E. The right weight: body fat, menarche and ovulation. Baillieres Clin Obstet Gynaecol. 1990 Sep;4(3):419–439. doi: 10.1016/s0950-3552(05)80302-5. [DOI] [PubMed] [Google Scholar]
  21. Haddow J. E., Palomaki G. E., Allan W. C., Williams J. R., Knight G. J., Gagnon J., O'Heir C. E., Mitchell M. L., Hermos R. J., Waisbren S. E. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19;341(8):549–555. doi: 10.1056/NEJM199908193410801. [DOI] [PubMed] [Google Scholar]
  22. Haggerty J. J., Jr, Garbutt J. C., Evans D. L., Golden R. N., Pedersen C., Simon J. S., Nemeroff C. B. Subclinical hypothyroidism: a review of neuropsychiatric aspects. Int J Psychiatry Med. 1990;20(2):193–208. doi: 10.2190/ADLY-1UU0-1A8L-HPXY. [DOI] [PubMed] [Google Scholar]
  23. Haggerty J. J., Jr, Prange A. J., Jr Borderline hypothyroidism and depression. Annu Rev Med. 1995;46:37–46. doi: 10.1146/annurev.med.46.1.37. [DOI] [PubMed] [Google Scholar]
  24. Henderson B. E., Bernstein L. The international variation in breast cancer rates: an epidemiological assessment. Breast Cancer Res Treat. 1991 May;18 (Suppl 1):S11–S17. doi: 10.1007/BF02633520. [DOI] [PubMed] [Google Scholar]
  25. Hergenroeder A. C. Bone mineralization, hypothalamic amenorrhea, and sex steroid therapy in female adolescents and young adults. J Pediatr. 1995 May;126(5 Pt 1):683–689. doi: 10.1016/s0022-3476(95)70393-4. [DOI] [PubMed] [Google Scholar]
  26. Hulka B. S. Epidemiologic analysis of breast and gynecologic cancers. Prog Clin Biol Res. 1997;396:17–29. [PubMed] [Google Scholar]
  27. Judd S. J. Disturbance of the reproductive axis induced by negative energy balance. Reprod Fertil Dev. 1998;10(1):65–72. doi: 10.1071/r98024. [DOI] [PubMed] [Google Scholar]
  28. Kaye T. B. Hyperprolactinemia. Causes, consequences, and treatment options. Postgrad Med. 1996 May;99(5):265–268. [PubMed] [Google Scholar]
  29. Kelsey J. L., Whittemore A. S. Epidemiology and primary prevention of cancers of the breast, endometrium, and ovary. A brief overview. Ann Epidemiol. 1994 Mar;4(2):89–95. doi: 10.1016/1047-2797(94)90052-3. [DOI] [PubMed] [Google Scholar]
  30. Klein N. A., Soules M. R. Endocrine changes of the perimenopause. Clin Obstet Gynecol. 1998 Dec;41(4):912–920. doi: 10.1097/00003081-199812000-00017. [DOI] [PubMed] [Google Scholar]
  31. Koutras D. A. Disturbances of menstruation in thyroid disease. Ann N Y Acad Sci. 1997 Jun 17;816:280–284. doi: 10.1111/j.1749-6632.1997.tb52152.x. [DOI] [PubMed] [Google Scholar]
  32. Laakso M., Lehto S. Epidemiology of risk factors for cardiovascular disease in diabetes and impaired glucose tolerance. Atherosclerosis. 1998 Apr;137 (Suppl):S65–S73. doi: 10.1016/s0021-9150(97)00314-6. [DOI] [PubMed] [Google Scholar]
  33. Laatikainen T. J. Corticotropin-releasing hormone and opioid peptides in reproduction and stress. Ann Med. 1991;23(5):489–496. doi: 10.3109/07853899109150508. [DOI] [PubMed] [Google Scholar]
  34. Lagrew D. C., Jr, Morgan M. A., Nakamoto K., Lagrew N. Advanced maternal age: perinatal outcome when controlling for physician selection. J Perinatol. 1996 Jul-Aug;16(4):256–260. [PubMed] [Google Scholar]
  35. Li S., Lanuza D., Gulanick M., Penckofer S., Holm K. Perimenopause: the transition into menopause. Health Care Women Int. 1996 Jul-Aug;17(4):293–306. doi: 10.1080/07399339609516246. [DOI] [PubMed] [Google Scholar]
  36. Loucks A. B., Laughlin G. A., Mortola J. F., Girton L., Nelson J. C., Yen S. S. Hypothalamic-pituitary-thyroidal function in eumenorrheic and amenorrheic athletes. J Clin Endocrinol Metab. 1992 Aug;75(2):514–518. doi: 10.1210/jcem.75.2.1639953. [DOI] [PubMed] [Google Scholar]
  37. Mansfield M. J., Emans S. J. Adolescent menstrual irregularity. J Reprod Med. 1984 Jun;29(6):399–410. [PubMed] [Google Scholar]
  38. Mascie-Taylor C. G. Endemic disease, nutrition and fertility in developing countries. J Biosoc Sci. 1992 Jul;24(3):355–365. doi: 10.1017/s002193200001991x. [DOI] [PubMed] [Google Scholar]
  39. McGee C. Secondary amenorrhea leading to osteoporosis: incidence and prevention. Nurse Pract. 1997 May;22(5):38, 41-5, 48 passim. [PubMed] [Google Scholar]
  40. McGrady A. V. Effects of psychological stress on male reproduction: a review. Arch Androl. 1984;13(1):1–7. doi: 10.3109/01485018408987495. [DOI] [PubMed] [Google Scholar]
  41. McIver B., Gorman C. A. Euthyroid sick syndrome: an overview. Thyroid. 1997 Feb;7(1):125–132. doi: 10.1089/thy.1997.7.125. [DOI] [PubMed] [Google Scholar]
  42. Meigs J. B., Nathan D. M., Wilson P. W., Cupples L. A., Singer D. E. Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance. The Framingham Offspring Study. Ann Intern Med. 1998 Apr 1;128(7):524–533. doi: 10.7326/0003-4819-128-7-199804010-00002. [DOI] [PubMed] [Google Scholar]
  43. Morley J. E., Melmed S. Gonadal dysfunction in systemic disorders. Metabolism. 1979 Oct;28(10):1051–1073. doi: 10.1016/0026-0495(79)90010-6. [DOI] [PubMed] [Google Scholar]
  44. Naylor C. D. Diagnosing gestational diabetes mellitus. Is the gold standard valid? Diabetes Care. 1989 Sep;12(8):565–572. doi: 10.2337/diacare.12.8.565. [DOI] [PubMed] [Google Scholar]
  45. Neidhart M. Prolactin in autoimmune diseases. Proc Soc Exp Biol Med. 1998 Apr;217(4):408–419. doi: 10.3181/00379727-217-44251. [DOI] [PubMed] [Google Scholar]
  46. Plagemann A., Harder T., Kohlhoff R., Rohde W., Dörner G. Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes. Diabetologia. 1997 Sep;40(9):1094–1100. doi: 10.1007/s001250050792. [DOI] [PubMed] [Google Scholar]
  47. Plagemann A., Harder T., Kohlhoff R., Rohde W., Dörner G. Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Relat Metab Disord. 1997 Jun;21(6):451–456. doi: 10.1038/sj.ijo.0800429. [DOI] [PubMed] [Google Scholar]
  48. Prior J. C., Vigna Y. M., Barr S. I., Rexworthy C., Lentle B. C. Cyclic medroxyprogesterone treatment increases bone density: a controlled trial in active women with menstrual cycle disturbances. Am J Med. 1994 Jun;96(6):521–530. doi: 10.1016/0002-9343(94)90092-2. [DOI] [PubMed] [Google Scholar]
  49. Pugliese A., Vicedomini D., Arsieri R. Esiti perinatali di neonati da madre ultraquarantenne. Uno studio caso-controllo. Minerva Ginecol. 1997 Mar;49(3):81–84. [PubMed] [Google Scholar]
  50. Rabinovici J. The differential effects of FSH and LH on the human ovary. Baillieres Clin Obstet Gynaecol. 1993 Jun;7(2):263–281. doi: 10.1016/s0950-3552(05)80130-0. [DOI] [PubMed] [Google Scholar]
  51. Redmond G. P. Androgens and women's health. Int J Fertil Womens Med. 1998 Mar-Apr;43(2):91–97. [PubMed] [Google Scholar]
  52. Reichman N. E., Pagnini D. L. Maternal age and birth outcomes: data from New Jersey. Fam Plann Perspect. 1997 Nov-Dec;29(6):268-72, 295. [PubMed] [Google Scholar]
  53. Rezende K. F., Melo A., Pousada J., Rezende Z. F., Santos N. L., Gomes I. Neuropatia vegetativa em pacientes com tolerância diminuída a glicose. Arq Neuropsiquiatr. 1997 Dec;55(4):703–711. doi: 10.1590/s0004-282x1997000500005. [DOI] [PubMed] [Google Scholar]
  54. Roccella E. J., Bowler A. E., Horan M. Epidemiologic considerations in defining hypertension. Med Clin North Am. 1987 Sep;71(5):785–801. doi: 10.1016/s0025-7125(16)30808-2. [DOI] [PubMed] [Google Scholar]
  55. Rodriguez M. M., Grossberg G. T. Estrogen as a psychotherapeutic agent. Clin Geriatr Med. 1998 Feb;14(1):177–189. [PubMed] [Google Scholar]
  56. Ross D. S. Hyperthyroidism, thyroid hormone therapy, and bone. Thyroid. 1994 Fall;4(3):319–326. doi: 10.1089/thy.1994.4.319. [DOI] [PubMed] [Google Scholar]
  57. Ruilope L. M., García-Robles R. How far should blood pressure be reduced in diabetic hypertensive patients? J Hypertens Suppl. 1997 Mar;15(2):S63–S65. doi: 10.1097/00004872-199715022-00005. [DOI] [PubMed] [Google Scholar]
  58. Sauer M. V. Pregnancy wastage and reproductive aging: the oocyte donation model. Curr Opin Obstet Gynecol. 1996 Jun;8(3):226–229. [PubMed] [Google Scholar]
  59. Schachter M., Shoham Z. Amenorrhea during the reproductive years--is it safe? Fertil Steril. 1994 Jul;62(1):1–16. doi: 10.1016/s0015-0282(16)56808-3. [DOI] [PubMed] [Google Scholar]
  60. Schaison G., Durand F., Mowszowicz I. Effect of glucocorticoids on plasma testosterone in men. Acta Endocrinol (Copenh) 1978 Sep;89(1):126–131. doi: 10.1530/acta.0.0890126. [DOI] [PubMed] [Google Scholar]
  61. Scheen A. J. Le risque cardio-vasculaire lié á l'hypercholestérolémie: d'un continuum à la notion de normalité, de seuil d'intervention et d'objectif thérapeutique. Rev Med Liege. 1999 Jan;54(1):17–21. [PubMed] [Google Scholar]
  62. Sheehan D. M., Willingham E., Gaylor D., Bergeron J. M., Crews D. No threshold dose for estradiol-induced sex reversal of turtle embryos: how little is too much? Environ Health Perspect. 1999 Feb;107(2):155–159. doi: 10.1289/ehp.99107155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Sherwin B. B. Estrogenic effects on memory in women. Ann N Y Acad Sci. 1994 Nov 14;743:213–231. doi: 10.1111/j.1749-6632.1994.tb55794.x. [DOI] [PubMed] [Google Scholar]
  64. Silverman B. L., Rizzo T. A., Cho N. H., Metzger B. E. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care. 1998 Aug;21 (Suppl 2):B142–B149. [PubMed] [Google Scholar]
  65. Smith K. D., Rodriguez-Rigau L. J., Tcholakian R. K., Steinberger E. The relation between plasma testosterone levels and the lengths of phases of the menstrual cycle. Fertil Steril. 1979 Oct;32(4):403–407. doi: 10.1016/s0015-0282(16)44295-0. [DOI] [PubMed] [Google Scholar]
  66. Surks M. I., Ocampo E. Subclinical thyroid disease. Am J Med. 1996 Feb;100(2):217–223. doi: 10.1016/s0002-9343(97)89462-4. [DOI] [PubMed] [Google Scholar]
  67. Turner H. E., Wass J. A. Gonadal function in men with chronic illness. Clin Endocrinol (Oxf) 1997 Oct;47(4):379–403. doi: 10.1046/j.1365-2265.1997.2611108.x. [DOI] [PubMed] [Google Scholar]
  68. Van der Spuy Z. M. Nutrition and reproduction. Clin Obstet Gynaecol. 1985 Sep;12(3):579–604. [PubMed] [Google Scholar]
  69. Wilder R. L. Hormones, pregnancy, and autoimmune diseases. Ann N Y Acad Sci. 1998 May 1;840:45–50. doi: 10.1111/j.1749-6632.1998.tb09547.x. [DOI] [PubMed] [Google Scholar]
  70. Woeber K. A. Subclinical thyroid dysfunction. Arch Intern Med. 1997 May 26;157(10):1065–1068. [PubMed] [Google Scholar]
  71. Woolley C. S., Schwartzkroin P. A. Hormonal effects on the brain. Epilepsia. 1998;39 (Suppl 8):S2–S8. doi: 10.1111/j.1528-1157.1998.tb02601.x. [DOI] [PubMed] [Google Scholar]
  72. von Schoultz B., Söderqvist G., Cline M., von Schoultz E., Skoog L. Hormonal regulation of the normal breast. Maturitas. 1996 May;23 (Suppl):S23–S25. doi: 10.1016/0378-5122(96)01007-9. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES