**3.1. Progestins**

or behavioral features, and so the two stages are usually grouped under the designation of "heat". Estrus is a transitional stage. Owing to the preovulatory luteinization of the granulosa cells in the growing follicles (progesterone levels increase above 2 ng/mL from LH peak onwards), early in this stage occurs a shift in the steroid environment, which changes from peaking estrogens to the progesterone dominance that will be maintained throughout diestrus. These changes induce a decrease in the amount of vaginal discharge, which also becomes more mucous and less hemorrhagic. In this stage, the female search more actively and the contact with the male and allows mating. Estrus lasts in average 9 days, but individual variations account for a range of 3–21 days. The LH surge occurs usually 24 h after the onset of estrus, but ovulation will take another 1.5–2.5 days to occur. The ovulation product is an immature oocyte that needs an additional period of 2–3 days for tubal maturation before fertilization [6].

Diestrus represents a prolonged luteal stage, similar in length whether or not pregnancy occurs. The decrease of progesterone levels below 1–2 ng/mL is often used to delimit the end of diestrus, as externally no clinical signs allow establishing the limits between diestrus and anestrus. Still, some bitches may present a residual mucous vaginal discharge or mammary development during diestrus that are absent in anestrus. The mean length of nongestational diestrus is 60 ± 15 days, while the gestational diestrus lasts for 63 ± 1 days. The levels of progesterone are already high at the diestrus onset; the peak is maintained for almost half the stage and gradually decreases by the end of this stage; the progesterone decline is more abrupt

In anestrus, the sex steroids are maintained in basal values, except in the last third of the stage, when the initial development of a wave of follicles in the ovaries occurs, thereby inducing a small increase in estrogens [13, 14]. Although this stage is often considered a time of reproductive quiescence, in fact in the uterus an important remodeling and repairing of the endometrium occurs, which is of upmost importance to the bitch fertility [13]. The length of this stage is the most variable in dogs, despite the reported average length of 18–20 weeks. The minimum length of anestrus is 7 weeks after the progesterone drop, but it can reach up to 10 months [6, 7]. It is important to remember, however, that the duration of the anestrus may be modulated by external environmental factors. An anestrous bitch can be stimulated to resume proestrus when in close proximity to a bitch in estrus [7]. This in fact contributes to the

synchronization of estrous cycles often observed when bitches are housed together.

Lately, in most developed countries, a variety of possible contraceptive methods became available. Thus, allowing the owner of a female dog or the practitioner to adopt the plan that best suits a particular individual or situation, by weighting the owner's aims for treatment, the physiological condition of the bitch and the expected side effects of the selected method. However, in a significant number of countries, progestins may remain the option of choice,

in gestational cycles than in nonpregnant ones [6, 8].

142 Canine Medicine - Recent Topics and Advanced Research

**3. Nonsurgical contraceptive options**

mainly due to economic constraints.

Progestins (synthetic progesterone-like compounds, also known as progestogens) remained for long time the unique available medical contraceptive option in dogs. Intended for a shortterm estrus suspension or postponement, chronic treatments longer than 2 years usually increase the negative effects that these drugs exert over the endocrine axis and the reproductive tract of the bitch.

Progestins are widely used, although these substances present major detrimental side effects in dogs, whose sensitivity to prolonged progesterone is high and predispose to uterine and mammary diseases [16]. This is a major drawback for the progestins use, particularly in chronic administration protocols or whenever the administration timing and doses are not followed adequately.

Progestins place the female under a prolonged artificial luteal stage. A constant supply of progestins causes the gonadotropin-releasing hormone ( GnRH) down-regulation, which in turn depress the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion, therefore suspending the follicular development in the ovaries. Also, progestins change the viscosity of the tubal and uterine secretions, and reduce the motility in the reproductive tract, compromising the transport of gametes and eggs and ruining the receptivity for a potential embryo [17]. Progestin actions are directly related to their side effects, as summarized in **Figure 2**.

The importance of the reactions to progestins administration increases the risk for a disease. This risk vary with: (1) the drug, its dose, the via of administration, and the frequency/length of the treatment; (2) the stage of the estrous cycle at the onset of treatment; and (3) some individual variations in sensitivity to the progestins that may be related to the age of the female (females older than 5 years are poor candidates for progestin treatment), existing pathologies or predispositions. Therefore, before starting any progestin treatment, the female should be subjected a thorough clinical examination. A careful and detailed anamnesis will allow to ascertain whether the female is postpubertal and in anestrus, whether the female is intended to breed within a 2-years period or eventually to understand if the owner will discontinue the treatment after a period of 18–24 months of progestin administration [4, 18] and willing to allow a full-term pregnancy to minimize the deleterious effects of progestins.

**Figure 2.** Summary of the main actions of progestins and the corresponding detrimental side effects in dogs.

The physical and reproductive examination will allow excluding pregnancy and obesity or any clinical evidence of hepatic, uterine, mammary, or metabolic disease, which might be exacerbated by the progestin treatment [17]. A female that is already in the proestrus stage is also a poor candidate for a progestin treatment, despite that these drugs might be (exceptionally) administered in the first day of heat [18]. The onset of treatment at the beginning of the follicular stage will increase the risks of pyometra [17] or mammary diseases.

There are several available progestins in the veterinary market, resulting from the research for less harmful products for dogs. However, the progestogen formulations approved for dogs may vary with the country. According to the chemical composition, progestins present different antigonadotrophic, gestagenic, and antiestrogenic properties that also define different risk potential. Older drugs (for instance, medroxyprogesterone acetate or megestrol acetate) usually possess stronger gestagenic actions and therefore more powerful negative side effects on the uterus and mammary glands than recent generation products, like proligestone.

In general, the particularities of the canine estrous cycle demand a different schedule for administration of oral progestins aiming the suspension of heat or the suppression of the estrous cycle. Thereby, in this species, the administration of progestins is more frequent as an injectable formula. However, it is important to know the length of the interestrous interval of a particular bitch and to adjust the subcutaneous administration of sequential progestins to avoid the breakdown effect (i.e., failure to control the cycle and by consequence the bitch enters in heat during the interval between administrations). Moreover, it should also be important to adjust the dose to the actual body weight, particularly in females of large and giant breeds.

Progestins available in the market for dogs include:





## **3.2. Androgens**

**Figure 2.** Summary of the main actions of progestins and the corresponding detrimental side effects in dogs.

follicular stage will increase the risks of pyometra [17] or mammary diseases.

Progestins available in the market for dogs include:

144 Canine Medicine - Recent Topics and Advanced Research

The physical and reproductive examination will allow excluding pregnancy and obesity or any clinical evidence of hepatic, uterine, mammary, or metabolic disease, which might be exacerbated by the progestin treatment [17]. A female that is already in the proestrus stage is also a poor candidate for a progestin treatment, despite that these drugs might be (exceptionally) administered in the first day of heat [18]. The onset of treatment at the beginning of the

There are several available progestins in the veterinary market, resulting from the research for less harmful products for dogs. However, the progestogen formulations approved for dogs may vary with the country. According to the chemical composition, progestins present different antigonadotrophic, gestagenic, and antiestrogenic properties that also define different risk potential. Older drugs (for instance, medroxyprogesterone acetate or megestrol acetate) usually possess stronger gestagenic actions and therefore more powerful negative side effects on the uterus and mammary glands than recent generation products, like proligestone. In general, the particularities of the canine estrous cycle demand a different schedule for administration of oral progestins aiming the suspension of heat or the suppression of the estrous cycle. Thereby, in this species, the administration of progestins is more frequent as an injectable formula. However, it is important to know the length of the interestrous interval of a particular bitch and to adjust the subcutaneous administration of sequential progestins to avoid the breakdown effect (i.e., failure to control the cycle and by consequence the bitch enters in heat during the interval between administrations). Moreover, it should also be important to adjust the dose to the actual body weight, particularly in females of large and giant breeds.


Few studies exist on the use of androgens as estrus suppressor in dogs. The oral administration of androgens is described for methyl testosterone (25 mg/dog, once a week [2]), orandrone (0.5 mg/kg, daily [20]), methyl testosterone associated with ethinylestradiol (7 mg/kg, daily, for 5– 10 days.[20]), and mibolerone, a synthetic weak androgen (Cheque Drops, at a dose of 30–180 mcg/day, starting 30 days before the onset of heat; it should not be administered for more than 2 years [7]). Injectable androgen therapeutic options include the intramuscular administration of testosterone cypionate (1 mg/kg, every 2 weeks [22]), testosterone phenylpropionate (110 mg/dog, weekly or alternatively at 0.5–1 mg/kg, every 7–10 days [2] and [20], respectively) or a composition of four different testosterone esters (Durateston®, at a dose of 2.5–5 mg/kg every 6 months [20]).
