Estrogen

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Estrogens (primarily estradiol 17-β and estrone) are the main endogenous estrogens synthesized primarily by the ovaries, and to a lesser extent by the testicles, adrenal cortex, placenta, liver, muscle, fat and hair follicles[1].

Estrogens are synthesized from androstenedione and testosterone, and are necessary for many physiological actions in the body including:

  • normal growth and development of female gonads
  • development of secondary sexual characteristics including duct growth of the mammary glands
  • changes in body conformation and hair growth
  • production of clinical signs of estrus
  • normal contractility of the uterus
  • promotion of bactericidal activity of the uterus during estrus by increasing the rate of migration of leucocytes into the uterine lumen
  • sensitization of the uterine muscle to oxytocin, relaxation of the pelvic structures, softening of the pubic symphysis and enlargement of general perineal area during parturition
  • regulation of skeletal growth and maintenance of the skeleton
  • vasostimulation and health of the skin
  • increasing the coagulability of the blood[2]

Synthetic estrogens such as diethylstilboestrol, stilboestrol and ethyloestrenol exert the same effect as natural estrogens and are used in female dogs for the treatment of mesalliance, estrogen-responsive incontinence in ovariohysterectomized dogs[3] and occasionally pseudopregnancy[4].

Recommended dose rate of diethylstilboestrol in dogs is 0.1 mg orally once weekly after an initial loading dose of 0.1 mg orally daily for 3 days.

In male dogs, it has been used for prostatic hyperplasia, anal adenomas and Sertoli cell tumors[5].

In entire bitches, diethylstrilboestrol induced polyfollicular changes in the ovary, increase oocyte production[6], and is therefore of use in cases of anestrus[7], conception failure and synchronization of ovulation for embryo transfer programs[8].

The primary side-effect of diethylstilboestrol is bone marrow hypoplasia and subsequent leucocytosis, nonregenerative anemia and thrombocytopenia. As the bone marrow suppression continues, leucopenia is observed 3 weeks post treatment in estrogen-sensitive dogs.

The bone marrow hypoplasia is thought to occur as a result of estrogen-induced production of a myelopoiesis-inhibitory factor by thymic stromal cells[9][10]. Some dogs may have fatal bone marrow suppression, whereas others have only mild to moderate damage after the administration of the same dose[11].

Other side-effects include feminization syndrome in neutered dogs, and development of pyometra when diethylstilboestrol is used at more than one dose for mesalliance[12]. Safer drugs such as aglepristone have replaced the use of diethylstilboestrol for this condition.

A differential diagnosis of diethylstilboestrol-induced myelosuppression includes toxins, neoplasia, immune-mediated anemia, immune-mediated thrombocytopenia, myelodysplasia, bone marrow necrosis, osteosclerosis and myelofibrosis.

Treatment of diethylboestrol toxicity include periodic fresh blood or platelet-rich transfusions, broad-spectrum antibiotics, steroids and bone marrow stimulants such as testosterone or nandrolone[13].

Stilboestrol-induced bone marrow suppression has been shown to be reversed with the use of lithium carbonate at 11 mg/kg orally twice daily for 6 weeks[14].

In untreated cases, the prognosis of dogs with EIM is always considered to be unfavorable, despite early diagnosis. Death from estrogen toxicity frequently occurs from complications of hemorrhage and infection

References

  1. Roberts SJ (1986) The estrogens. In: Roberts SJ, editor. Veterinary Obstetrics and Genital Diseases. Woodstock, Vermont: Roberts SJ. pp:403–405
  2. Sontas HB et al (2009) Estrogen-induced myelotoxicity in dogs: A review. Can Vet J 50(10):1054-1058
  3. Hill K et al (2012) Medical therapy for acquired urinary incontinence in dogs. Int J Pharm Compd 16(5):369-375
  4. Gobello C et al (2001) A review of canine pseudocyesis. Reprod Dom Anim 36:283–288
  5. McDonald LE (1988) Estrogens. In: Booth NH, McDonald LE, editors. Veterinary Pharmacology and Therapeutics. 6th ed. Ames, Iowa: Iowa State Univ; Pr. pp:598–604
  6. Reynaud K et al (2010) Polyovular follicles. Gynecol Obstet Fertil 38(6):395-397
  7. Bouchard GF 'et al (1993) Oestrus induction in the bitch with the synthetic oestrogen diethylstilboestrol. J Reprod Fertil Suppl 47:515-516
  8. Kutzler MA (2005) Induction and synchronization of estrus in dogs. Theriogenology 64(3):766-775
  9. Farris GM & Benjamin SA (1993) Inhibition of myelopoiesis by conditioned medium from cultured canine thymic cells exposed to estrogens. Am J Vet Res 54:1366–1373
  10. Farris GM & Benjamin SA (1993) Inhibition of myelopoiesis by serum from dogs exposed to estrogen. Am J Vet Res 54:1374–1379
  11. Crafts RC (1948) The effects of estrogens on the bone marrow of adult female dogs. Blood 3:276–285
  12. Tsutsui T et al (2006) Estradiol benzoate for preventing pregnancy in mismated dogs. Theriogenology 66:1568–1572
  13. Acke E et al (2003) Estrogen toxicity in a dog. Ir Vet J 56:465–468
  14. Hall EJ (1992) Use of lithium for treatment of estrogen-induced bone marrow hypoplasia in a dog. J Am Vet Med Assoc '200(6):814-816