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Basics ⬇

Basics

Overview

  • A syndrome characterized by high serum concentration of estrogens (estradiol, estriol, or estrone).
  • Can occur as a result of excessive estrogen secretion, accumulation or administration of exogenous estrogens, such as diethylstilbestrol or estriol.
  • Sites of endogenous estrogen production include ovarian follicles, follicular ovarian cysts, Leydig cells, and the adrenal cortex (zona glomerulosa and fasciculata); can also occur as a result of peripheral conversion of excessive androgens.
  • Endogenous estrogens in the female are responsible for normal sexual behavior and development and function of the female reproductive tract; in the male, estrogens are responsible for Leydig cell function.
  • Estrogens potentiate the stimulatory effect of progesterone in the endometrium and permit cervical relaxation; these two effects increase the risk of cystic endometrial hyperplasia and pyometra. In the male, estrogens potentiate the action of androgens in the prostate. Estrogens also increase osteoblastic activity, retention of calcium and phosphorus, total body protein and metabolic rate.
  • High serum concentration of estrogen provides a source of negative feedback in the hypothalamic-pituitary axis and results in suppression of gonadotropin secretion; interferes with stem cell differentiation in the bone marrow and erythrocyte iron metabolism.

Signalment

Endogenous Hyperestrogenism

  • Older male dog (secondary to functional testicular tumors).
  • Older female dog (secondary to granulosa cell tumors or other functional ovarian tumor types, follicular ovarian cysts).
  • Young female dog (follicular ovarian cysts).

Exogenous Hyperestrogenism

  • All breeds, genders, and ages in association with estrogen administration or exposure.
  • Toy breed dogs are at increased risk when exposed to transdermal hormone replacement therapy.

Signs

Historical Findings

  • Attractive to intact male dogs.
  • Infertility.
  • Prolonged proestrus and estrus (female).
  • Decreased libido (male).
  • Nymphomania (female).
  • Variable vulvar bleeding and enlargement causing excessive vulvar licking.
  • Epistaxis, hematuria if thrombocytopenic; lethargic, febrile if neutropenic; lethargic if anemic.

Physical Examination Findings

  • Skin/Endocrine-non-pruritic, symmetric alopecia (endocrine alopecia), hyperpigmentation.
  • Reproductive (male)-palpable testicular mass; testicular asymmetry (in association with a tumor mass and/or testicular atrophy); testicular atrophy: may be unilateral atrophy in the non-tumor-containing testicle, as seen in association with a functional estrogen-producing testicular tumor, or bilateral, as seen in association with exogenous hyperestrogenism; cryptorchidism (unilateral or bilateral) should be ruled out; prostatomegaly (secondary to squamous metaplasia); gynecomastia. The testicular tumor can replace most of the normal testicular tissue if advanced.
  • Reproductive (female)-vulvar edema and enlargement; variable vulvar discharge depending on the presence of residual uterine tissue; gynecomastia.
  • Hemic/Lymphatic/Immune-pale mucous membranes; thrombocytopenic hemorrhage; petechia; fever (due to secondary bacterial infection in association with neutropenia); depression.

Causes & Risk Factors

  • Follicular ovarian cysts.
  • Functional ovarian tumor (granulosa cell tumor and other ovarian tumors).
  • Testicular tumor (specifically Sertoli cell tumor, but also may occur secondary to Leydig and interstitial cell tumors).
  • Exogenous estrogen administration or exposure-iatrogenic.

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

Non-pruritic, Symmetric Alopecia (Endocrine Alopecia)

  • Hypothyroidism-diagnosis based on appropriate clinical signs in conjunction with typical hematologic and biochemical abnormalities (normocytic normochromic non regenerative anemia, hypercholesterolemia) and thyroid function testing (total T4, free T4, cTSH).
  • Hyperadrenocorticism-clinical signs usually include polyuria, polydipsia, and exercise intolerance; CBC may reveal leukocytosis and erythrocytosis; serum biochemistry abnormalities include elevated ALP, ALT, and cholesterol, and decreased BUN; additional testing includes urine cortisol creatinine ratio, ACTH stimulation, LDDS test (preferred), endogenous ACTH, abdominal ultrasonography.
  • GH-responsive dermatosis.

Attractive to Male Dogs

  • Vaginitis, perivulvar dermatitis-can be differentiated from hyperestrogenism via examination of vaginal cytology (lack of vaginal superficial epithelial cell predominance), lack of evidence of ovarian abnormalities, or confirmation of complete ovariohysterectomy or ovariectomy.
  • Genitourinary tract infection, inflammation (foreign body) or neoplasia.

Infertility

  • Testicular degeneration/atrophy/immune-mediated orchitis-diagnosis based on physical examination, lack of testicular or intra-abdominal masses, semen evaluation (azoospermia, teratospermia), and testicular FNA for cytology or testicular biopsy.
  • Intersex abnormalities-uncommon; diagnosis supported by physical examination findings (abnormal external genitalia), abnormal karyotype, and histologic examination of the reproductive tract, where available.

CBC/Biochemistry/Urinalysis

  • CBC-changes are extremely variable; if present, initial 2–3 weeks characterized by thrombocytopenia or thrombocytosis, progressive anemia, and leukocytosis (white cell counts may exceed 100,000 WBC/µL); after 3 weeks, pancytopenia and aplastic anemia may be noted; hematuria (secondary to thrombocytopenia).
  • Chemistry panel and urinalysis usually unremarkable.

Other Laboratory Tests

  • Serum estrogen (estradiol) concentrations-may be evaluated via radioimmunoassay; however, physiologic serum concentrations may be within normal limits due to accuracy of assay. Prolonged elevation (>30 days) of estradiol at levels expected for proestrus or estrus is responsible for the clinical signs rather than the actual level.
  • Vaginal/preputial cytology-extremely reliable as a bioassay for estrogen; under the influence of estrogen, will reveal a predominance of superficial epithelial cells that are anuclear or have pyknotic nuclei.
  • Evaluation for ovarian remnant syndrome (see Ovarian Remnant Syndrome).

Imaging/Endoscopy

  • Ultrasonography of the abdomen, inguinal canal, and testes-to assess for testicular masses, cystic or enlarged ovarian structures, intra-abdominal masses, prostatomegaly (not appropriate for a neutered dog), and regional lymph node size and echogenicity.
  • Vaginoscopy-can be completed to evaluate the vaginal mucosa; under the influence of estrogen, the vaginal mucosa should appear edematous and pink.

Diagnostic Procedures

  • Fine-needle aspiration for cytology of testicular masses-can provide a cytologic diagnosis prior to pursuing surgery.
  • Percutaneous ultrasound-guided aspiration of large ovarian follicular cysts rarely results in clinical resolution, as the cystic structure persists. The cystic fluid obtained can be evaluated for hormone concentration.
  • Three-view metastatic radiographic evaluation of the thoracic cavity-complete prior to any surgical intervention when neoplasia is suspected.
  • Complete hemogram, serum chemistries, and urinalysis-always perform preoperatively for cytopenias, hepatic dysfunction (estrogen metabolism).
  • Examination and biopsy of local lymph nodes-for evaluation of metastatic disease; can be completed, if indicated, at time of surgical exploration or performed with ultrasound guidance.
  • Bone marrow core biopsy-can confirm the presence of myelosuppression.
  • Laparoscopy or laparotomy-can be used to identify and remove intra-abdominal masses, ovarian tissue, or cryptorchid testicular tissue, followed with histopathology.
  • Skin biopsy-may reveal nonspecific changes associated with endocrine alopecia such as orthokeratotic hyperkeratosis, epidermal atrophy and melanosis, follicular keratosis, telogen hair follicles, and sebaceous gland atrophy.

Treatment ⬆ ⬇

Treatment

Medications ⬆ ⬇

Medications

Drug(s)

  • Supportive care-including administration of appropriate antimicrobial therapy and blood products.
  • Synthetic erythropoietin, darbopoietin, G-CSF, GM-CSF-may be considered to stimulate erythroid and granulocytic production at the level of the bone marrow; lithium has reportedly been of benefit in cases of estrogen-induced bone marrow aplasia.
  • GnRH-unlikely to induce ovulation in cases of follicular cysts.

Contraindications/Possible Interactions

Administration of chemotherapeutic agents for treatment of metastatic testicular or ovarian neoplasia should be pursued with caution due to increased risk of bone marrow suppression secondary to hyperestrogenism. Consult with a veterinary oncologist.

Follow-Up ⬆ ⬇

Follow-Up

Miscellaneous ⬆

Miscellaneous

Associated Conditions

  • Prostatomegaly metaplasia
  • Cystic-endometrial hyperplasia and subfertility
  • Hepatic insufficiency
  • Infertility
  • Bone marrow aplasia, pancytopenia
  • Sepsis
  • Ovarian remnant syndrome (see chapter)

Abbreviations

  • ACTH = adrenocorticotropic hormone
  • ALP = alanine phosphatase
  • ALT = alanine aminotransferase
  • G-CSF = granulocyte colony-stimulating factor
  • GH = growth hormone
  • GM-CSF = granulocyte-macrophage colony-stimulating factor
  • GnRH = gonadotropin-releasing hormone
  • hCG = human chorionic gonadotropin
  • LDDS = low-dose dexamethasone suppression
  • T4 = thyroxine
  • TSH = thyroid-stimulating hormone
  • WBC = white blood cell

Authors Autumn P. Davidson and Sophie A. Grundy

Consulting Editor Deborah S. Greco

Client Education Handout Available Online

Suggested Reading

Davidson AP, Reproductive System Disorders. In: Nelson RW, Couto GC, eds., Small Animal Internal Medicine, 5th ed. St Louis, MO: Elsevier, 2014, pp. 897–966.