*1.1.4. Drug-related anestrus*

Long-term use of some drugs, such as androgen and progestogens, causes anestrus by inhibiting cycles. Exogenous glucocorticoid administration is also reported to affect serum LH level and the normal cycle. Puberty is inhibited due to suppression of genital-canal development and ovarian activity in bitches that have undergone administration of long-acting GnRH agonists like deslorelin [15].

Similarly, cyclic activity may not be observed for a long time in prepubertal bitches that have been actively immunized against GnRH [16].

A comprehensive anamnesis should be obtained from the pet owner if drug-related anestrus is suspected; sufficient data must be obtained regarding the medical history of the bitch. If a pet owner has recently acquired the bitch and if he or she has no or insufficient information about previous vaccinations and medications, drug-related anestrus should always be considered. In such situations, the only treatment is to wait until the effects of the drug(s) disappear or until the antibody titration decreases, if immunized against GnRH.

## *1.1.5. Thyroid dysfunctions*

There is an indirect and strict association between thyroid dysfunction and reproductivity. Hypothyroidism leads to reproductive disorders such as prolonged anestrus, silent heat, prolonged proestrus, and ovulatory problems. The prolactin level increases, which leads to impair or no development of ovarian follicles by inhibiting GnRH in bitches that have insufficient thyroid hormone release [17].

In bitches, hypothyroidism usually manifests as primary hypothyroidism, resulting from destruction of the thyroid gland. The serum total and free thyroxin levels are low in bitches with thyroid dysfunction. Thyrotropin-releasing hormone (TRH) secretion from the hypothalamus increases due to low levels of thyroid hormones; consequently, thyroid-stimulating hormone (TSH) secretion from the pituitary gland increases. As a result of this totally physiological process, low serum total and free thyroxin levels and elevated serum TSH levels are observed in bitches with primary hypothyroidism [7].

Hypothyroidism should be kept in mind in the presence of numbness or mental fatigue, hair loss, weight increase or obesity, dryness or loss of body hair, hyperpigmentation, cold intolerance, bradycardia, high plasma cholesterol level, or anemia in a bitch with an anestrous problem. Measurement of only thyroid hormones may yield misleading or conflicting results. Therefore, a full thyroid profile should be obtained and a definitive diagnosis made in bitches suspected of hypothyroidism. For this purpose, the serum-free thyroid hormone level (particularly T4 measurement) and the response of the thyroid gland to TSH administrations should be investigated. Furthermore, autoantibodies against thyroxin (T4) and triiodothyronine (T3) or thyroglobulin should be investigated in serum, as they are produced in most bitches with lymphocytic thyroiditis [7, 18, 19].

The sexual cycle may return to normal with hormone replacement therapy within 3–6 months in bitches diagnosed with hypothyroidism. For this purpose, synthetic thyroid hormone (levothyroxin) should be administered through the peroral route. A dose of 22 μg/kg b.i.d. is usually sufficient.

Although hyperthyroidism with consequent primary anestrus is a rare condition in bitches, a case has been reported in a Pinscher dog with diet-related hyperthyroidism in which primary anestrus developed; the bitch reached proestrus 13 days later after dietary regulation, with estrus then induced by cabergoline [20].

## *1.1.6. Pituitary gland insufficiency*

The pituitary gland is important for the endocrinological functions of the adrenal glands, thyroid gland, and the ovaries. Abnormalities of the pituitary gland also negatively affect these organs. Prolonged anestrus is unusually seen in bitches with dwarfism caused by a congenital anomaly. Ovariohysterectomy is recommended in bitches that show prolonged anestrus related to pituitary gland insufficiency [6].

## *1.1.7. Systemic diseases*

Such diseases may negatively affect reproductive function. Cycles probably will not develop if an animal is unhealthy.

## *1.1.8. Ovarian anomalies*

Progesterone-releasing ovarian cysts, ovarian aplasia, and oophoritis may lead to primary anestrus. Definitive diagnosis can be made by histopathological examination of the ovarian tissue [21].
