Chlorinated Sugars: A Biochemical Approach to the Control of Male Fertility

Abstract

6‐Chloro‐6‐deoxyglucose (120 μmol; 24 mg kg b.wt.), 6‐chloro‐6‐deoxyfructose (< 240 μ 48 mg/kg b.wt.), 6‐chloro‐6‐deoxysucrose (240 μmol; 85 mg/kg b.wt.), ′6‐chloro‐′6‐deoxysucrose (< 240 μmol; 85 mg/kg b.wt.) and 6.′6‐dichloro‐6,′6‐dideoxysucrose (240 μmol; 89 mg/kg b.wt.) administered to male rats daily, by oral gavage, render them infertile after 7 days treatment. The effect is sustained through at least 4 weeks of treatment and is reversed 3 to 6 weeks after treatment is withdrawn. Spermatozoa from the cauda epididymidis of treated rats oxidize only 10% as much glucose as spermatozoa from controls and their ATP and total adenine nucleotide content fall more rapidly during incubation with 2 mM [U14C]D‐glucose. These biochemical effects are associated with a more rapid decline in cell motility. The LD50 for 6‐chloro‐6‐deoxyglucose in the rat is > 16 g/kg b.wt. Administration of [36Cl] ′6‐chloro‐′6‐deoxysucrose has shown this compound to be extensively dechlorinated in vivo. Chlorodeoxy sugars are discussed as potential male antifertility agents worthy of further investigation.

Effect of -chlorohydrin on glucose metabolism by spermatozoa from the cauda epididymidis of the rhesus monkey (Macaca mulatta)

“…However, the energy charge was identical to that found in monkey ejaculated spermatozoa (Hoskins et al, 1971) and similar to that observed in rat epididymal spermatozoa after incubation with glucose for 10 min (Ford & Waites, 1978).…”

“…However, high doses of -chlorohydrin are required to inhibit the oxidation of acetate, pyruvate or lactate by ram spermatozoa (Brown-Woodman et al, 1978). Moreover, spermatozoa from rats treated with 6-chloro-6-deoxyglucose (24 mg/kg/day), which has an antifertility effect similar to that of -chlorohydrin (Ford & Waites, 1978), can remain motile and retain a high energy charge when supplied with 2 mM-pyruvate plus 4 mM-DL-lactate as substrates although these parameters decline rapidly when 2 mM-glucose is the only substrate given (Ford & Waites, 1980). Therefore, unless spermatozoa are compelled to metabolize sugar at some stage, e.g.…”

Interference with Epididymal Physiology as Possible Site of Male Contraception

“…When spermatozoa from the cauda epididymidis of the treated rats were incubated in the presence of 2 mM uI4 C-D glucose, they oxidized only 10% as much glucose as spermatozoa from controls, and the levels of ATP and total adenine nucleotide content fell rapidly [18]. These biochemical effects are associated with a rapid decline in cell motility and fertility.…”

Orally administered ketoconazole rapidly appears in seminal plasma and suppresses sperm motility

“…Other agents with an epididymal site of action followed including cyproterone acetate and the 6-deoxy-6-halo sugars [21,22]. Although in animal studies antifertility effects could be reached in as little as 1 week from onset of dosing, toxicity or variable efficacy precluded further development of these agents [23][24][25].…”