N V

figure 14-23 Structure of bromocriptine (or 2-bromo-a-ergocryptine), an inhibitor of pituitary prolactin secretion.

in stature and exhibit undeveloped secondary sex characteristics and amenorrhea.

An individual with XXX chromosomes is designated as a "superfemale." This chromosomal aberration occurs approximately once in 1600 female births. There is also a wide spectrum of hermaphrodites that reflects the various problems that can arise from incorrect gonadal differentiation. A true hermaphrodite is an individual who possesses both testicular and ovarian tissues.

C. Breast Cancer

Breast cancer is the most prevalent malignancy in the United States, with 175,000 new cases occurring annually. Women have approximately a 1:9 lifetime chance of experiencing the disease. While the causes of breast cancer are not known, approximately 35% of cases are estrogen-dependent. Mammary tissue requires more endocrine factors for its structural development and regulation of its lactation function than virtually any other tissue; this includes estrogen and progesterone, prolactin, vasopressin, insulin, growth hormone, glucocorticoids, thyroxine, 1,25-di-hydroxyvitamin D3, and oxytocin. While it is conceivable that any or all of these hormones could mediate cell growth of a breast tumor, to date only estrogen, progesterone, and prolactin have been linked to malignant breast growth. The dramatic demonstration by Beatson in 1896 that mammary cancer regressed after bilateral oophorectomy in premenopausal women initiated the view that mammary tumors could be controlled by manipulating the endocrine environment. Jensen has shown a good correlation between the presence of an estrogen receptor in breast tumors and the likelihood of response to endocrine therapy. Approximately 66% of all breast tumors have significant levels of estrogen receptor. Such information is now utilized as part of the diagnostic evaluation of women with breast cancer; those premenopausal individuals who are estrogen receptor-positive become candidates for castration. Postmenopausal women who are estrogen receptor-positive are candidates for treatment with antiestrogens such as tamoxifen. Tamoxifen (see Figure 13-19) is a nonsteroidal competitive inhibitor of estradiol binding to the estrogen receptor. Tamoxifen is utilized as an oral drug for the treatment of postmenopausal women with advanced breast cancer. Regrettably in the human, endocrine therapy rarely achieves total extinction of the tumor and other management procedures, including chemotherapy or surgical procedures, must often be instituted.

D. Galactorrhea

Galactorrhea is defined as a persistent discharge from the breast of a milklike fluid that is not associated with parturition and lactation. Galactorrhea may occur as a consequence of a wide variety of endocrine and nonendocrine disorders; these endocrine-related instances include pituitary tumors, which produce prolactin, the Chiari-Frommel syndrome (which is defined as galactorrhea and amenorrhea persisting more than 6 months postpartum) in the absence of nursing, oral contraceptive usage, and primary hypothyroidism.

Serum levels of prolactin are usually elevated in galactorrhea. If the cause of the elevated plasma level of prolactin is an inappropriate secretion by the adeno-hypophysis, then the possibility of a pituitary tumor must be considered. In this instance, surgical removal or chemotherapy with drugs such as L-dopamine or the ergot alkaloid bromocriptine may be initiated. These two compounds interfere with prolactin secretion by the pituitary. The structure of bromocriptine is given in Figure 14-23.

References

A. Review Articles

Bryant-Greenwood, G. D., and Schwabe, C. (1994). Human relaxins:

chemistry and biology. Endocr. Rev. 15, 5-26. Cooke, N. E. (1995). Prolactin: basic physiology. In "Endocrinology" (M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds.), 3rd ed., Vol. 1, Chapter 23, pp. 368-393. W. B. Saunders Company, Philadelphia, PA. Ezrin, C., Godden, J. O., Volge, R., and Wilson, R. (1973). "Systematic

Endocrinology." Harper & Row, Hagerstown, MD. Gaddy-Kurten, D., Tsuchida, K., and Vale, W. (1995). Activins and the receptor serine kinase superfamily. In "Recent Progress in Hormone Research" C. W. Bardin, ed.), Vol. 50, pp. 109-129. Grumbach, M. M., Styne, D. M., Wilson, J. D„ and Foster, D. W. (1992). "Williams' Textbook of Endocrinology," 8th ed., pp. 11712. W. B. Saunders Company, Philadelphia, PA. Kierszenbaum, A. L. (1994). Mammalian spermatogenesis in vivo and in vitro: a partnership of spermatogenic and somatic cell lineages. Endocr. Rev. 15, 116-134. Lee, M. M., and Donahoe, P. K. (1993). Mtillerian inhibiting substance: a gonadal hormone with multiple functions. Endocr. Rev. 14, 152-164.

Odell, W. D. (1995). Genetic basis of sexual differentiation. In "Endocrinology" M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds.), Vol. 2, Chapter 107, pp. 1881-1887. W. B. Saunders Company, Philadelphia, PA.

Qu, J., and Thomas, K. (1995). Inhibin and activin production in human placenta. Endocr. Rev. 16, 485-507.

Strauss, J. F., Ill, Gafvels, M., and King, B. F. (1995). Placental Hormones. In "Endocrinology" L. J. DeGroot, M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds.), 3rd ed., Vol. 3, Chapter 124, pp. 2171-2206. W. B. Saunders Company, Philadelphia, PA.

Walker, W. H., Fitzpatrick, S. L., Barrera-Saldana, H. A., Resendez-Perez, D., and Saunders, G. F. (1991). The human placental lactogen genes: Structure, function, evolution, and transcriptional regulation. Endocr. Rev. 12, 316-328.

B. Research Articles

Beatson, G. T. (1896). On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment of inoperable cases of carcinoma of the mamma. Lancet 2, 162-164.

Berkovitz, G. D., Fechner, P. Y., Marcantonio, S. M., Bland, G., Stetten, G., and Goodfellow, P. N. (1992). The role of the sex-determining region of the Y chromosome (SRY) in the etiology of 46,XX true hermaphroditism. Human Genet. 88, 411-416.

Berta, P., Hawkins, J. R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., and Fellous, M. (1990). Genetic evidence equating SRY and the testis-determining factor. Nature 348, 448-450.

Haqq, C. M„ King, C. Y„ Donahoe, P. K., and Weiss, M. A. (1993). SRY recognizes conserved DNA sites in sex-specific promoters. Proc. Natl. Acad. Sci. USA 90, 1097-1101.

Hercz, P., Siklos, P., and Ungar, L. (1989). Quantitative comparison of serum steroid and peptide hormone concentrations in male and female fetuses in the maternal-fetoplacental system during the 28th-40th weeks of pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 30, 201-204.

Jahn, G. A., Edery, M., Ali, S., Belair, L., Kelly, P. A., and Djiane, J. (1991). Prolactin receptor gene expression in rat mammary gland and liver during pregnancy and lactation. Endocrinology 128, 2976-2984.

Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P. N., and Lovell-Badge, R. (1991). Male development of chromosomally female mice transgenic for SRY. Nature 351, 117-121.

McElreavey, K., Vilain, E., Abbas, N., Herskovitz, I., and Fellous, M. (1993). A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc. Natl. Acad. Sci. USA 90, 3368-3372.

Page, D. C., Mosher, R., Simpson, E. M., Fisher, E. M., Mardon, G., Pollack, J., McGillivray, B„ Chapelle, A. D. L., and Brown, L. G. (1987). The sex-determining region of the human Y chromosome encodes a finger protein. Cell 51, 1091-1104.

Palmer, M. S., Berta, P., Sinclair, A. H., Pym, B., and Goodfellow, P. N. (1990). Comparison of human ZFY and ZFX transcripts. Proc. Natl. Acad. Sci. USA 87, 1681-1685.

Rozakis-Adcock, M., and Kelly, P. A. (1990). Mutational analysis of the ligand binding domain of the prolactin receptor. J. Biol. Chem. 266, 16472.

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