Progestins

When progestins are given by serial administration or depot injection to bitches, the result is an artificial luteal phase that mimics many of the effects of the progesterone secreted during the 2-month luteal phase that normally follows ovulation in the ovarian cycle. Mechanisms include an antigonadotropic action potentially resulting in lowered luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulsatile secretion and plasma concentrations; an antiestrogen action achieved by reducing the concentrations of intracellular estrogen receptors in many tissues, including those regulating gonadotropin secretion; and progestational actions on the reproductive tract occurring out of the normal sequence of the ovarian cycle, resulting in altered endometrial growth and secretion, altered cervical secretion, reduced sperm transport, and altered uterine-tube motility. In addition, progestins can have an antiovulatory effect by preventing a preovulatory surge release of gonadotropins (LH and FSH) from the pituitary, the normal stimulus for ovulation, if administered before a large rise in estrogen. However, administration at or immediately after the follicular phase peak in estrogen can facilitate and advance the preovulatory LH surge and ovulation. When administered beginning several days or more before the peak in estrogen would have occurred, progestins typically prevent the LH surge, possibly by interfering with hypothalamic and pituitary responses to estrogen.

However, none of these actions provides an explanation of how the typical clinical administration of a progestin during anestrus causes an apparent prolongation of anestrus and prevents and delays the occurrence of a new ovarian follicular phase or an associated proestrus. Long-term progestin administration in bitches does not lower the systemic concentrations of LH below those typically observed during most of normal anestrus and actually may result in a small increase in basal LH (Colon et al, 1993), perhaps by acting as an antiestrogen and partially interfering with the normal negative feedback effects of estrogen.

During normal ovarian cycles, elevated progesterone reduces GnRH pulsatility, and thus reduces LH and FSH pulsatility. As a result, the luteal phase prevents any increase in gonadotropin pulsatility that would stimulate the next follicular phase. Contraceptive progestin treatment has the same effect. The progestin prevents any increase in gonadotropin pulsatility sufficient to initiate another estrus cycle. Why the effect lasts 1 to several months after withdrawal of progestin is not understood, but it is similar to what is observed after luteolysis during the normal ovarian cycle. In dogs, proestrus does not occur until after many weeks or months of an obligate anestrus after the end of the 7- to 10-week luteal phase and the decline in progesterone concentrations to nearly undetectable levels. A contraceptive progestin treatment mimics a luteal phase and postpones and reestablishes the onset of anestrus.

Androgens

The estrous cycle postponing effects of androgens, like those of progestins, appear to involve primarily a negative feedback effect at the level of the hypothalamus and possibly the pituitary. The contraceptive and other effects of androgens in females may be the same as in males by binding to androgen receptors or may involve cross-talk with other steroid receptors. Androgen receptors have been observed in estrogen target tissues, and androgen binding can result in reduced responsiveness to estrogen. The duration of effect after hormone withdrawal may vary among androgens. Androgen therapy including testosterone reportedly is followed often by rapid return to estrus within a few weeks after withdrawal (England, 1998), although some androgen therapy such as mibolerone typically has required 2 to 3 months for return to estrus, with a range of 1 to 7 months, as with progestins. In addition, termination of long-term androgen use in bitches, especially with testosterone, can result in a prolonged or even permanent anestrus, as observed in some racing greyhound bitches.

Megestrol Acetate Tablets

Megestrol acetate is marketed in North America as Ovaban tablets for the prevention and postponement of proestrus and estrus in anestrus bitches and for the curtailment of proestrus and prevention of ovulation and estrus in early proestrus bitches. Ovaban is marketed in bottles of 5- or 20-mg tablets for oral administration. The generic drug tablets are available in those sizes and others from compounding pharmacies. The recommended dosage is 0.55 mg/kg/day (or 0.25 mg/lb/day) for 32 days in anestrus bitches. Higher dosages of 2.2 mg/kg/day (or 1 mg/lb/day) for 8 days are given to bitches already in early proestrus. The indication is for use in adult bitches for up to two successive cycles. In some countries, including the United Kingdom, megestrol acetate is used in pubertal dogs as well as adults. Diabetes mellitus, mammary tumors, uterine disease, and liver disease are contraindications to the use of megestrol acetate. Bitches with an unknown or ill-defined reproductive history should be confirmed to be in anestrus by vaginal cytology and progesterone assay before treatment. Administration during pregnancy can result in masculinization of female fetuses. Treatment should not be repeated beyond two successive estrous cycles without allowing an intervening normal cycle.

Administration during anestrus should be initiated 1 to 2 weeks or more before the next expected proestrus. If initiated too late in anestrus, a spontaneous proestrus may occur and require changing to the higher, proestrus-regimen dosing. If treatment is started immediately before the onset of proestrus, the subsequent proestrus may occur a few weeks after withdrawal. If megestrol acetate is initiated too early in anestrus, there may be no apparent postponement of the next cycle. The next proestrus typically occurs 4 to 6 months after treatment, with a range of 1 to 7 months. The advantages of the oral formulation are ease of administration and administration by the owner; concerns include compliance by the owner and potential for underdosing or overdosing. The bitch’s body weight should be determined with exactitude, and the precise number of tablets or partial tablets of a specific formulation to be administered each day should be provided with written instructions.

Administration of megestrol acetate in early proestrus should begin within 3 days of proestrus onset. Client education regarding the signs of early proestrus is important. A bitch with a normal proestrus usually lasting less than 4 days or longer than 20 days is reportedly not a good candidate for megestrol acetate treatment during proestrus. Early proestrus status can be confirmed by vaginal cytology showing less than 50% superficial cells, increasing rather than decreasing vulval turgidity, and serum progesterone concentrations less than 0.5 ng/ml. Proestrus treatment with megestrol acetate should be combined with isolation of the bitch from males for 3 to 8 days and until the end of serosanguineous discharge, following the recommendation of the manufacturer. The suppression of proestrus symptoms occurs by 3 to 8 days after initiation of treatment. The subsequent proestrus is expected in 4 to 6 months but ranged from 1 to 7 months in clinical trials. Administration too late in proestrus can likely result in induction of ovulation, failure to prevent ovulation, or the occurrence of estrus.

Megestrol acetate is currently the only cycle preventive or estrus preventive marketed for dogs in the United States and is approved for use in two successive cycles. In the United Kingdom similar dosages of megestrol acetate (Ovarid) are recommended, including 0.55 mg/kg/day for 40 days in anestrus, or 2 mg/kg/day for 8 days in early proestrus. However, for the bitch in pubertal proestrus, or with a history of pseudopregnancy, or housed with other bitches and susceptible to pheromone effects, the recommendation has been to use a dose of 2 mg/kg for 4 days and then 0.55 mg/kg for 16 days. The onset of proestrus must be determined accurately for use in proestrus, especially in pubertal bitches. The treatment of bitches in anestrus also includes the option to continue treating with lower doses of 0.2 mg/kg twice weekly for up to 4 months after the initial 40 days of treatment but then allowing a normal estrus to occur before retreating. The 40-day regimen also can be followed with an early proestrus treatment at the next estrous cycle.

In other countries, generic megestrol acetate is marketed under many brand names for use in dogs and/or cats in tablets of various content (5, 10, or 20 mg), sometimes of a single content (10 mg). The 10-mg tablets can make it difficult to dose accurately smaller animals. The drug should be administered according to the manufacturer’s recommendation, unless assuming that a lower dose or shorter period of treatment will be effective is reasonable based on recommendations of other manufacturers or review articles. Side effects in dogs most frequently mentioned by manufacturers include increased appetite and weight gain, decreased aggression, increased docility, and mammary enlargement. Megestrol acetate tablets also are marketed as a human product (Megace).

Megestrol acetate at the higher proestrus dose also has been proposed and used to prevent the induction of proestrus at the onset of a treatment with a GnRH-agonist subcutaneous implant administered for long-term estrus suppression (see below).