The »early-Androgen« Syndrome; Differences in Response to Pre-Natal and Post-Natal Administration of Various Doses of Testosterone Propionate in Female and Male Rats

Abstract

The interaction between dose and time of administration of testosterone propionate (TP) on the development of sexual function was studied by giving a single dose of 5, 10, 50 or 500 μg TP to young rats of both sexes on the day of birth (day 1) or on day 2, 4 or 5. The effectiveness of androgen administration before birth was studied by giving a single injection of 2500 μg TP to pregnant rats on day 19 to 22 after conception. Pre-natal administration had no effect on the function of the ovaries of female offspring, although the dose was sufficient to cause masculinization of the external genitalia. The weight of the testes and accessories of the male offspring were not affected. The effects of post-natal TP administration on ovarian function varied with the dose and with the time of administration. Threshold doses (5 and 10 μg) were more effective the earlier they were given after birth. With these small doses, most of the rats had normal luteinized ovaries at 10 weeks and were able to bear and suckle normal litters. Some time later ovulations ceased so that at 21 weeks they were no longer fertile; at 27 weeks there were no more corpora lutea in the ovaries. In males, a dose of 50 μg of TP or more resulted in permanently reduced weight of testes, seminal vesicles and prostate. The earlier the treatment, the more marked was the depression of weight. From these results and others reported in the literature the following deductions can be made: (1) the critical period of brain sensitivity to physiological amounts of androgen probably lies between days 4 and 6 (day of birth counted as day 1); (2) a rough estimate of the amount of androgen secreted by the newborn male rat during the critical period would seem to be the equivalent of a single injection of 5–50 μg TP; (3) after the physiological critical period has elapsed a female rat can still be »masculinized« if a high dose of TP is given, up to a period of between 10–20 days after birth.

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…In the absence of fetal imprinting, the pubertal activation of sex-specific mating behaviors never occurs [43,116]. Furthermore, not only is puberty important for activational effects of steroid hormones on neonatally imprinted circuits [12,153,16,116,119], but the brain may be sensitive to the organizational effects of steroid hormones during this developmental stage [119,129,39,144]. Matsumoto and Arai showed substantial neural development, as manifested by neurite outgrowth, in the hypothalamus of pubertal animals, and further, that this process was stimulated by exogenous hormone exposure [96,7].…”

Pathology of Vaginal Atresia in BALB/cA-<I>nu</I>/+and BALB/cA-<I>nu</I>/<I>nu</I> Mice

“…The irregular endometrium is observed in the same condition in inbred mice [3] and seems to be attributable to deviation from the normal figure of estrus cycle [1,7]. Alterations noticed in the ovary of the present cases have not been described in mice affected with vaginal atresia, but have been recognized in rats affected with this disorder caused by neonatal androgeninjection [8,9]. The unrelated cyclic changes in the ovary, endometrium and vaginal mucosa in the present cases suggest a hormonal disorder.…”

Rodent models of polycystic ovary syndrome

“…A single postnatal treatment of rats with TP during the first 5 days of life completely blocked [23,25,[29][30][31][32] or significantly reduced their ability to ovulate [23]. Rats exposed to TP in the first 5 days of life resulted in persistent anovulatory estrus [33], whereas TP exposure on Day 1 or 5 also caused acyclicity and polycystic ovaries with atretic follicles, cystic follicles exhibiting thin granulosa cell layers [30][31][32]34], and increased production of estrogens (estrone [E1] and E2) and androgens (T and A4) [34].…”

“…Although 1 study reported that exposure of rodent fetuses to testosterone propionate (TP) by intra-amniotic administration induced anovulation in 64% of rats [21], in most studies, prenatal treatment of mice with T [22] or rats with TP [21,[23][24][25][26][27] had no effect on cyclicity or ovarian function, inferred by the presence of follicles at various stages and corpora lutea. A detailed study by Wu et al [28] showed that prenatal treatment of rats with T on Days 16 and 19 of gestation resulted in irregular estrous cycles and an ovarian phenotype of increased numbers of preantral and antral follicles but a decrease in preovulatory follicle and corpus lutea populations.…”

“…2 and 3). However, care must be taken when comparing models, as age of analysis had an effect on the observed phenotype, with differences in the presence of cysts or corpora lutea observed [26,45] in most but not all studies [25]. Prenatal exposure can lead to vaginal fusion, and although researchers have varied doses of androgens to minimize this effect [38], this is a significant limitation of this model for evaluation of fertility, which is a key feature of PCOS.…”