Alternative methods for feline fertility control

Abstract

Practical relevance:

Reversible contraceptives are highly desired by purebred cat breeders for managing estrous cycles and by scientists managing assisted reproduction programs. A variety of alternative medicine approaches have been explored as methods to control feline fertility.

Scope:

In the field of veterinary homeopathy, wild carrot seed and papaya have been used for centuries. Both appear to be safe, but their efficacy as feline contraceptives remains anecdotal. In contrast, the use of melatonin in cats has been investigated in a number of studies, findings from which are reviewed in this article.

Rationale:

Cats are seasonally polyestrous (they cycle several times during their breeding season) and are described as long-day breeders because endogenous melatonin negatively regulates estrous cyclicity. Exogenous melatonin administered parenterally also suppresses ovarian activity in cats, and long-term oral or subcutaneous melatonin administration is safe.

Challenges:

The therapeutic use of melatonin is limited by its short biological half-life (15–20 mins), its poor oral bioavailability and its central effects in reducing wakefulness. Research is required to determine whether higher doses, longer-release formulations, repeated administration or combination implants might overcome these limitations.

Melatonin – the rationale

Reversible contraceptives are highly desired by purebred cat breeders for managing estrous cycles and by scientists managing assisted reproduction programs. Artificial insemination (AI) has significant potential for improving the ex situ management and conservation of wild felid populations. ¹ Suppressing endogenous ovarian activity before AI or in vitro fertilization/embryo transfer improves pregnancy rates in the domestic cat. ² Short-term pharmacologic control of the feline estrous cycle is most commonly accomplished using progestins despite potential undesirable side effects associated with high doses of these compounds (eg, cystic endometrial hyperplasia–pyometra complex, mammary fibroadenomatosis, mammary neoplasia, hyperglycemia–glucosuria syndrome due to insulin resistance). ³ As the interestrus interval in unmated cycling queens is 9.0 ± 7.6 days during the breeding season,^4,5 administration of exogenous melatonin to suppress ovarian activity is an attractive option.

Melatonin (5-methoxy-N-acetyltryptamine) is a tryptophan-derived neurohormone produced by the pineal gland in a circadian rhythm of secretion, with greater concentrations during darkness. ⁶ The pineal gland is a neural organ with multifunctional significance in modulating endocrine control and synchronizing physiologic functions with internal and external conditions. ⁷ Melatonin exerts its action through two membrane-associated (high affinity G-protein coupled) receptors (MT1 and MT2), ⁸ which are present in neuronal and non-neuronal tissues. ⁹ Within the brain, MT1 and MT2 receptors are located in the suprachiasmatic nucleus (the ‘central clock’), which is responsible for the effect of melatonin on circadian rhythms.^{10 –12} In the cat, rhythms for both arginine vasopressin and melatonin are endogenously generated within the suprachiasmatic nucleus and entrained by the light–dark cycle. ¹³

The role of the pineal gland and melatonin in mammalian physiology has been previously reviewed. ¹⁴ While the effects of melatonin in other species are beyond the scope of this current review, melatonin has been extensively studied in other seasonal species for estrous cycle control. ¹⁵

The domestic cat is a seasonal long-day breeder, meaning that reproductive activity is influenced by photoperiod. In the northern hemisphere, ovarian activity typically ceases in October under decreasing photoperiod and resumes in January with increasing photoperiod. ¹⁶ Reducing the photoperiod to 8 h of light inhibits folliculogenesis in queens. ¹⁷ Cats cease estrous cyclicity immediately when the photoperiod is reduced from 14 h to 8 h, and estrous cycles resume in 12–26 days (15.6 ± 0.5 days) after the photoperiod is increased from 8 h to 14 h.^17,18 The immediate suppressive effects of melatonin on follicular growth may be mediated through a cytoplasmic receptor, ¹⁹ which could directly interfere with estrogen synthesis. Melatonin has also been shown in one study to decrease the amount of luteinizing hormone (LH) released in response to mating. ²⁰ However, 67% of cats followed in the study ovulated despite changes in LH. ²⁰

Melatonin – the evidence base

Decreasing photoperiod is related to high endogenous melatonin concentrations, which are then followed by decreased sexual activity. Exogenous melatonin can be used to mimic this situation. Either oral or parenteral administration of exogenous melatonin or melatonin receptor agonists will suppress feline reproductive function. The dose, frequency and route of administration as well as the reproductive outcome determined by melatonin research in cats are summarized in Table 1.

Table 1

Dose, frequency and route of administration of exogenous melatonin administered to female and male cats and associated reproductive outcomes

Sample size (n)	Dose and route of administration	Cycle stage at initiation of treatment	Outcome	Reference
16 females	5 mg q48h SC	Not stated	Suppressed ovarian activity even under a 24 h light photoperiod for 60 days	20
6 females	30 mg q24h PO 3 h before lights off for 35 days	Not stated	Returned to estrus 33 ± 2.8 days (range 21–40 days) after treatment ended	2
4 females	60 mg (five 12 mg implants)	Not stated	Suppressed estrus in 75% (duration of estrus suppression not given)	21
9 females	18 mg (single implant)	During interestrus	Within 3–9 days of implant insertion, 33% had superficial cells present on their vaginal cytology and estrous behavior for 2 days followed by estrus suppression for 4 months	22
9 females	18 mg (single implant)	During estrus	Within 9–11 days of implant insertion, 78% had superficial cells present on vaginal cytology and estrous behavior for 2–3 days followed by estrus suppression for 2 months	22
12 females	4 mg/cat q24h PO until onset of estrus	During interestrus	Prolonged interestrus (interval between onset of treatment and first estrous cycle was 50 ± 6.1 days)	23
17 females	18 mg (single implant)	During interestrus	Prolonged interestrus (interval between onset of treatment and first estrous cycle was 51 ± 4.7 days)	23
4 males	18 mg (single implant)	Not applicable	100% significantly decreased their sperm quality until 120 ± 15 days after implant insertion	24
12 females	18 mg (single implant)	Prepubertally	Did not delay puberty	23
10 females	4 mg/cat q24h PO until onset of estrus	Prepubertally	Did not delay puberty	23

SC = subcutaneous, PO = oral

Oral treatment

Oral melatonin treatment (30 mg q24h for 30 days) prior to an estrus induction protocol for AI only marginally reduced ancillary follicle development. ² The authors speculated that a longer duration of melatonin treatment may provide greater inhibition of ovarian activity. ² It is important to note that this treatment had no significant effect on the quantity or quality of embryos produced by AI, thus demonstrating its safety for this application. ² With the exception of one case report of cystic endometrial hyperplasia following administration of a melatonin implant, ²¹ no other side effects have been reported.^4,22 Although the uterus has not been specifically evaluated in melatonin- treated cats, some treated females have been bred following treatment and have become pregnant, demonstrating the likelihood of normal uterine integrity and future fertility. ²³ In addition, when administered prepubertally, melatonin does not affect growth.

However, oral melatonin treatment is unlikely to reliably suppress fertility unless it is administered at a set time of the day (around 2 h before darkness). Such a treatment may not be realistic in field conditions because cats dislike oral administration and compliance with treatment delivered at a set time of the day may be limited. The advice to practitioners, therefore, is not to contemplate this option.

Subcutaneous implants

Prolonged-release subcutaneous formulations of melatonin have been tested in cats as a more practical option than oral administration.^{21 –23} The interscapular space is commonly used as an implant insertion site, and the implant can be administered in an unsedated patient with local infiltration of anesthetics. Melatonin implants (18 mg, Melovine; Ceva Santé Animale) are commercially available for veterinary use in several countries, whereas melatonin tablets are readily available over the counter in pharmacies and health food stores worldwide. In sheep, subcutaneous melatonin implants maintain constant serum melatonin concentrations, unlike oral melatonin administration. ²⁵ Data demonstrating constant melatonin concentrations following implant placement in cats are lacking, but the effect is presumed to be similar to that seen in sheep.

Results concerning efficacy (rapid and prolonged estrous cycle suppression) with melatonin implants have not been consistent among reports, possibly due to the variability in the timing of implant administration relative to the onset of estrus or time of year. For example, estrus suppression for about 2–4 months following administration of melatonin implants ranged from 100% (9/9 cats, 18 mg implants) ²² to 50% (2/4 cats, 12 mg implants). ²³ Although the sample sizes are small, these data suggest that ovarian responses to melatonin implants are dose-related. ²³ In addition, some studies demonstrate an immediate effect,^17,21 while other studies report a 5–30 day delay prior to estrus suppression.^2,20,22

Delayed estrus suppression using melatonin may be an artefact of a lack of detailed estrous cycle monitoring before the implant was administered, as administration of melatonin during estrus results in a rapid return to estrus.^22,23 High estrogen concentrations have previously been shown to interfere with responses to both endogenous and exogenous melatonin. ²⁶ High serum estradiol concentrations decrease expression of melatonin ovarian receptors via downregulation in rats^27,28 and humans.^{29 –31} It is not known whether queens have ovarian melatonin receptors; if they do, this could explain the shorter interestrus interval observed when melatonin implants are administered during estrus. ²² Having said this, the primary action of melatonin in suppressing reproductive activity in the cat is centrally mediated.

Melatonin receptor agonists

Several melatonin receptor agonist compounds are available but only a few have been investigated in cats. The oral administration of compound 4D (0.1 mg/kg) results in a sleep-promoting action in cats, but reproductive activity was not reported. ³⁷ Ramelteon is an MT1/MT2 receptor agonist for the treatment of insomnia and circadian rhythm disorders in humans. Oral administration of ramelteon (0.001, 0.01 and 0.1 mg/kg) has also been investigated in cats. ⁹ Ramelteon decreased wakefulness for up to 6 h, whereas exogenous melatonin (1.0 mg/kg PO) only reduced wakefulness for 2 h. ⁹ Although both male and female cats were evaluated in this study, there was no information provided about reproductive effects.

Melatonin – the challenges

The therapeutic use of melatonin is limited by its short biological half-life (15–20 mins), its poor oral bioavailability and its ubiquitous action. Indeed, the chronobiotic effects of melatonin have led to many therapeutic targets in humans such as sleep disorders, ³⁸ neurodegenerative diseases,^39,40 cancer^41,42 and stroke. ⁴³ In the cat, melatonin can be a useful tool for the treatment of uveitis. ⁴⁴

The cat has proven to be a very useful model for studying the sleep-promoting action of melatonin and its receptor agonists. ⁹ Doses of exogenous melatonin in excess of 1 mg/kg affect wakefulness. ⁹ However, the mechanisms behind the sleep-promoting effects of melatonin are still unknown. ⁹ GABA-A receptors are widely distributed in the suprachiasmatic nucleus and may serve both presynaptic and postsynaptic roles in controlling mammalian circadian rhythms.^45,46 These effects can be reversed by GABA-A receptor antagonists. ⁴⁷ Thus, the sleep- promoting action of melatonin might be derived from responses of the GABAergic system in the suprachiasmatic nucleus. ⁹

What to conclude?

Long-term melatonin administration is safe, but this treatment only results in short-term estrus suppression in postpubertal cats; it has not been effective in prepubertal cats. ²³ Some view the short estrous cycle suppression in cats induced by melatonin as insufficient, ²³ leaving opportunities for researchers to investigate ovarian effects from higher melatonin doses, a longer-release formulation or repeated administrations. As prolactin release is also higher during darkness in the female cat, ⁴⁸ and both melatonin and prolactin secretion are very responsive to changes in photoperiod in the cat, ⁴⁹ it is likely that the two hormones are involved in modulating the responsiveness of the hypothalamus to the negative feedback effects of estrogen. ⁴⁹ Implants containing a combination of melatonin and prolactin may provide superior estrous cycle suppression compared with melatonin alone.

Key Points

• Exogenous melatonin administered parenterally has short-term effects of suppressing ovarian activity in cats.

• Therapeutic use of melatonin is limited by its short biological half-life (15–20 mins), its poor oral bioavailability and its central effects in reducing wakefulness.

• Long-term subcutaneous melatonin administration is safe in cats and repeated administration of melatonin implants may extend contraceptive efficacy.