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Prenatal Androgens Time Neuroendocrine Puberty in the Sheep: Effect of Testosterone Dose¹

Reproductive Sciences Program and Departments of Biology (S.S.K., C.H.-E., D.L.F.) and Obstetrics and Gynecology (D.L.F.), University of Michigan, Ann Arbor, Michigan 48109-0404; and the Department of Obstetrics and Gynecology, Yale University (R.I.W.), New Haven, Connecticut 06520-8063

Address all correspondence and requests for reprints to: Dr. Douglas L. Foster, Room 1101, 300 North Ingalls Building, Ann Arbor, Michigan 48109-0404. E-mail: dlfoster{at}umich.edu

	Abstract

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In sheep, prenatal exposure to androgens during a critical period for sexual differentiation of the brain (30–90 days of gestation; 145 days is term) can advance the timing of puberty in females and prevent the preovulatory LH surge. The present study tests the hypothesis that in sheep, the timing of neuroendocrine sexual maturation is related to the amount of prenatal steroid exposure. In addition, we determined if different steroid requirements exist for sexual differentiation of the tonic and surge modes of gonadotropin secretion. Testosterone was administered weekly to three groups of pregnant ewes from days 30–90 of gestation at doses of 200, 80, or 32 mg/week. The resulting androgenized female lambs together with control males and females (n = 5–7/group) were gonadectomized at 3 weeks of age, and gonadal steroids were replaced with a SILASTIC brand estradiol-filled capsule. LH concentrations were measured from biweekly blood samples. Sustained increases in circulating LH were considered to reflect the initiation of neuroendocrine puberty. In male lambs, LH secretion started to increase at 8.3 ± 0.9 weeks of age (mean ± SEM). The two highest doses of prenatal androgen advanced the onset of neuroendocrine sexual maturation in females. In the 200 mg androgenized females, the pubertal LH rise (10.2 ± 2.0 weeks) began about the same time as in males. In the 80 mg treatment group, LH concentrations increased at 16.2 ± 1.5 weeks, which was later than in males, but well before that in normal females (27.1 ± 0.7 weeks). For females treated with the lowest dose of androgen (32 mg), the pubertal LH increase (24.6 ± 1.9 weeks) began about the same time as in normal females. To test the function of the LH surge system, LH was measured every 2 h for 60 h after an acute increase in circulating estradiol was produced by implanting additional estrogen capsules. All control females produced a surge in response to acute estradiol stimulation. LH surges did not occur in males, 200 mg androgenized females, or 80 mg androgenized females. Of six females from the 32 mg treatment group, two produced LH surges in response to the stimulatory feedback action of estradiol. We conclude that the greater the amount of prenatal testosterone, the earlier the initiation of the pubertal LH rise. Moreover, the finding that low doses of testosterone (32 mg/week) are capable of abolishing the LH surge without significantly advancing the timing of puberty supports our hypothesis that different steroid requirements exist for sexual differentiation of tonic and surge modes of LH secretion.

	Introduction

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IN MAMMALIAN and avian species, sexual differentiation of the neuroendocrine system plays a critical role in the behavioral and hormonal differences between the sexes (reviewed in Ref.1). In sheep (2) as well as many other species (reviewed in Ref.1), the preovulatory LH surge resulting from the stimulatory feedback of estradiol is sexually differentiated. Females respond to increasing circulating estradiol with a massive discharge of LH, but this same response is normally neither present nor inducible in males (2). We have recently determined that tonic LH secretion is also sexually differentiated (3). Unlike the surge system, however, tonic LH secretion is common to both sexes. Sex differences arise in the timing of increased tonic LH secretion that initiates the onset of sexual maturity. While males begin their sustained increase in tonic LH secretion at approximately 10 weeks of age, females remain hypogonadotropic until approximately 30 weeks. This pubertal rise in LH is a result of a decrease in sensitivity to estradiol negative feedback (reviewed in Ref.4).

Sex differences in tonic and surge modes of gonadotropin secretion arise from androgens acting during a prenatal critical period of development, when the brain is susceptible to the organizing actions of gonadal steroids. The early studies of Short (5) and Clarke et al. (6) on androgenized female sheep determined that the critical period for sexual differentiation of the LH surge system is 30–90 days gestation (145 days is term). More recent studies from our laboratory (7, 8) have confirmed these findings (5, 6, 9). Of equal interest, we have determined that exposure to androgens during this same period masculinizes the control of tonic LH secretion to advance the timing of puberty.

An emerging concept of prenatal steroid action is that separate steroid requirements exist for the differentiation of tonic and surge modes of LH secretion in the sheep. The developing neuroendocrine system may be sensitive to the timing, dose, and identity (androgen vs. estrogen) of steroid in utero. A previous study from our laboratory (8) determined that a longer duration of androgen exposure is required for masculinization of the LH surge compared to that for masculinization of tonic LH. The present study investigated the effects of androgen dose. Female lambs were androgenized from days 30–90 of gestation with three doses of testosterone. After birth, the timing of onset of neuroendocrine sexual maturation and the responsiveness to the stimulatory feedback of estradiol were characterized in these androgenized females and compared to those in normal males and females.

	Materials and Methods

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Animals
The method used to obtain masculinized female lambs was identical to that used in our earlier study (7), except that the dose of testosterone was varied to delineate the influence of amount of steroid on the developing brain. Three groups of pregnant Suffolk ewes with known conception dates received nine weekly injections of testosterone cypionate at doses of 200, 80, and 32 mg/week (in 1.0 ml cottonseed oil, im; Sigma Chemical Co., St. Louis, MO) between approximately 30 and 90 days gestation (term is 145 days). Whereas testosterone treatment at a dose of 100 mg/week induces variable masculinization of the genitalia and tonic LH (7), weekly injections of 200 mg testosterone are sufficient for complete masculinization of neuroendocrine function (8). The 80- and 32-mg doses of testosterone used in the present study each represent a 2.5-fold reduction from the next highest dose. The time of testosterone treatment in utero spanned the critical period for sexual differentiation of the LH surge mechanism established by Short (5) and Clarke et al. (6) and our laboratory (7, 8).

Males (n = 7), females (n = 5), and three groups of androgenized females (200 mg group, n = 5; 80 mg group, n = 6; 32 mg group, n = 6) with a mean (± SEM) birth date of April 5 ± 1.2 days were used. At 1 week of age, these lambs along with their mothers were transported to the Reproductive Sciences Program Sheep Research Facility in Ann Arbor from the breeder (Wallen Farm, Hubbard Lake, MI). All lambs were housed outdoors with their mothers until weaning. At 8 weeks of age, the lambs were weaned and raised on a commercial pelleted diet containing 20% protein, supplemented with vitamins, minerals, and alfalfa hay to maintain a rapid growth rate. Water was available at all times. Body weights were determined weekly and are plotted in Fig. 1.

View larger version (38K): [in this window] [in a new window]   Figure 1. Growth of males (filled squares), females (filled circles), and androgenized females (open symbols) during the experimental time period.

Tonic LH
Beginning at 2 weeks of age, 5-ml blood samples were collected by jugular venipuncture twice weekly throughout the 40-week experimental period to monitor changes in LH secretion. Samples were allowed to coagulate overnight, serum was decanted and then frozen until assayed for LH by RIA. The timing of neuroendocrine puberty in gonadectomized, estradiol-treated lambs was determined from the pattern of circulating LH concentrations according to a criterion established previously in our laboratory (15). The onset of the pubertal rise was defined as the age when the first of six consecutive LH samples (3 weeks) exceeded 1 ng/ml. This age was compared among the five groups using ANOVA, and post-hoc comparisons were made using Scheffe’s F test (Statview SE⁺ Graphics, Brainpower, Calabasas, CA).

LH surge
The influence of prenatal androgen dose on the positive feedback system postpubertally was studied in androgenized females along with control males and females using an identical paradigm as that in our previous studies (16, 17). To maximize the amplitude of LH release, the single estradiol capsule was removed when the lambs reached about 40 weeks of age. Three weeks later, the surge induction protocol was begun. Blood samples (5 ml) were collected every 2 h for 12 h before and 60 h after implantation of four 30-mm SILASTIC estradiol capsules (described above). This estrogen treatment produces high physiological levels of the steroid (12 pg/ml) and is sufficient to induce a LH surge in normal female lambs (18). Two criteria established previously by our laboratory (19) were used to define a LH surge. First, circulating LH concentrations must be sustained above the pretreatment baseline for at least 8 h (four samples). Second, the peak concentration of LH must exceed at least twice the average of the preestradiol treatment concentration. The incidence of surges was compared between the groups using Scheffe’s F test (Statview SE⁺ Graphics, Brainpower). ² analysis was used to compare the proportion of animals in the various prenatal treatment groups responding to the stimulatory feedback action of estradiol with a LH surge.

LH assay
LH was measured in duplicate 25- to 200-µl aliquots using modifications (20, 21) of a RIA developed by Niswender et al. (22, 23). The assay sensitivity, as defined by 2 standard deviations from maximum binding, was 0.87 ng/ml for 200 µl serum (16 assays) expressed relative to NIH LH-S12. Intraassay coefficients of variation, determined from two quality control pools of 20% and 80% on the standard curve, averaged 7.5% and 16.7%, respectively; the interassay coefficient of variation averaged 17.5%.

	Results

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External genitalia
Schematic views of the external genitalia of males, females, and representative androgenized females are presented in Fig. 2. The 200-mg dose of testosterone masculinized the external genitalia of females producing a penis and an empty scrotum as in our previous study (8). However, these females had a significant (P < 0.05) posterior displacement of the penis compared to normal males. Females receiving the intermediate testosterone dose of 80 mg in utero were partially masculinized. All possessed a split scrotum, with the urethral opening lying between the two empty scrotal folds. The vulvae were considerably turgid in these females. The position of the urethral opening lay between that for normal males and females, but significantly more posterior than that in the 200 mg treatment group. The 32-mg dose of testosterone produced minimal masculinization of the external genitalia. Although the vulvae were slightly turgid, these females were otherwise indistinguishable from untreated females. The position of the urethral opening was similar to that for normal females. In none of the androgenized females were any obvious abnormalities found in the uterus or ovaries upon gross visual inspection at the time of ovariectomy. There were no significant differences in body weight between male and female lambs during the course of this study (Fig. 1). Moreover, as reported previously (7), prenatal exposure to androgens had no effect on body weight during the first 30 weeks of life.

View larger version (27K): [in this window] [in a new window]   Figure 2. Effects of prenatal testosterone on the external genitalia of postnatal female lambs viewed from the left as sagittal hind quarter diagrams of a normal male (top), female (bottom), and representative androgenized females (middle); the penis and scrotum are shaded. Indicated is the mean (±SEM) position of the urethral opening (penis or vulva) relative to the distance between the anus (0) and the navel (1).

View larger version (31K): [in this window] [in a new window]   Figure 3. Timing of neuroendocrine sexual maturity in normal males (top), females (bottom), and androgenized females (middle). LH concentrations are represented as the mean ± SEM per group. Closed arrowheads indicate the average age at initiation of sexual maturity for the group. Open arrowheads indicate the timing of a sustained increase in LH above 1 ng/ml for each individual.

LH surge
Figure 4 depicts the pattern of LH secretion in response to the stimulatory feedback effects of estradiol in representative lambs from each group. Exogenous estradiol produced LH surges in all five normal females, and LH concentrations increased to a peak of 131.4 ± 20.2 ng/ml. In four of five females, the peak of the LH surge occurred synchronously at 18.5 ± 1.0 h, a time comparable to that in our previous studies using the identical surge-inducing paradigm (19). However, one female (no. 551) did not increase LH secretion until 50 h after the beginning of estradiol treatment. She was considered to be a physiological outlier because of this long latency period; when her data were included, the overall mean time was 24.8 ± 6.3 h. Surges were absent in all normal males (n = 7). Like males, none of the 200 mg (n = 5) and 80 mg (n = 5) androgenized females produced a LH surge during the 72-h sampling period. However, the 32 mg androgenized females showed variability in their responses to estradiol, with most being unable to produce a LH surge. Of the six females in this group, LH concentrations were never sustained above pretreatment levels in four animals. The remaining two females produced LH surges at 26 (92 ng/ml) and 40 (51 ng/ml) h after estradiol treatment. As a group, the proportion of 32 mg females responding (two of six) was not different from that of the 200 mg androgenized females or males (no response, P > 0.05).

View larger version (57K): [in this window] [in a new window]   Figure 4. Representative patterns of LH secretion in response to acute estradiol stimulation in gonadectomized males, females, and androgenized females. At 0 h, four estradiol implants were inserted to raise circulating levels to approximately 12 pg/ml. Blood samples were collected for 12 h before and 60 h after steroid administration. Shading indicates the average LH concentration before estradiol treatment.

	Discussion

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The developing neuroendocrine system may be sensitive to the timing, dose, or type of steroid (androgen vs. estrogen) in utero. In addition, tonic and surge modes of gonadotropin secretion may be differentially responsive to each of these factors. Our previous study of androgenized lambs investigated the importance of timing. By subdividing the putative 60-day critical period for sexual differentiation of gonadotropin secretion (30–90 days gestation) into smaller segments, we determined that tonic and surge modes of LH secretion can be differentially influenced by the timing of prenatal steroid exposure (8). For lambs exposed to androgens early (30–51 days) or late (65–86 days) in gestation, it was possible to advance the timing of neuroendocrine sexual maturation without preventing the LH surge. Females exposed to androgens throughout the full 60-day period, however, had a defeminized surge system as well as an advanced neuroendocrine puberty. However, in that study of the timing of androgen exposure, the amount of steroid was confounded with the duration of steroid treatment. That is, a longer duration of steroid treatment resulted in a greater total steroid exposure. Because it is reasonable to expect that the developing neuroendocrine system is also sensitive to the amount of steroid exposure, our current experiment focused solely on dose.

The combined findings from our current study of dose and our previous study of timing (8) begin to provide some understanding about the organization of the LH surge system by prenatal steroids. From our timing study, females treated with testosterone early (30–51 days) or late (65–86 days) in the critical period could produce LH surges in response to exogenous estradiol. The total amount of testosterone (800 mg) provided to those females in utero was roughly equivalent to the total amount administered to the current 80 mg treatment group (720 mg from days 30–90). However, the LH surge was abolished in all of the current 80 mg treated females. These considerations suggest that defeminization of the LH surge is highly dependent on the duration of testosterone exposure. It seems that exposure during the entire critical period (30–90 days gestation) is necessary to organize central mechanisms to render the LH surge system inoperable after birth. The early and late treatment groups used previously were each only exposed to testosterone during a portion of this developmental window, and consequently, the LH surge remained functional. However, the current 80-mg treatment covered a much broader time interval, the entire critical period, and abolished the function of the LH surge mechanism postnatally.

On the other hand, the amount of steroid, within the range of doses tested, is much less important for the defeminization of the surge system. Both the current 200- and 80-mg testosterone treatments defeminized the surge mechanism. The finding that the LH surge was not functional in most (four of six) animals in the 32-mg treatment group suggests that the steroid threshold required for defeminization is relatively low. Small amounts of steroid are capable of abolishing the surge as long as they are present from 30–90 days gestation. Therefore, it seems that the duration of exposure, and not the dose of steroid, is critical for defeminizing the LH surge.

The prenatal organizational action of steroids on the postnatal control of tonic LH secretion seems more complex. From our previous study (8), females treated with testosterone in utero early (30–51 days) or late (65–86 days) in the critical period had an intermediate advancement in the onset of neuroendocrine sexual maturity (19–20 weeks of age). The current 80 mg treatment group, with a similar steroid dose but for the full duration of the critical period (prenatal days 30–90), also produced an intermediate advancement in neuroendocrine puberty at approximately 16 weeks of age. Such results suggest that neither timing nor dose plays a commanding role in the sexual differentiation of tonic LH secretion. Rather, it seems that masculinization of tonic LH is an integration of both timing and amount. Testosterone exposure for a short duration at high doses is not sufficient for complete masculinization of tonic LH, as shown by the early and late treatment groups (8). Moreover, exposure to a low dose of testosterone for an extended period is not sufficient for masculinization, as evidenced by the failure to advance the timing of the pubertal LH rise in the current 32 mg treatment group. Similarly, the intermediate 80-mg treatment, although sufficiently long in duration, was also too small an amount of steroid to completely masculinize tonic LH mechanisms. For complete masculinization, a high amount of testosterone over an extended time is necessary. This is exemplified by the pubertal rise in LH secretion occurring as in males at about 10 weeks of age both in the long term treated females from our previous study (200 mg, days 30–90) and in the identical treatment group from the current study. Therefore, both duration and amount of testosterone contribute to the masculinization of the control of tonic LH secretion.

Little is known about the identity of steroid responsible for sexual differentiation of the surge system. The actions of fetal testosterone can be androgenic through direct action or reduction to dihydrotestosterone or estrogenic through aromatization to estrogen (reviewed in Ref.1). Although in the rodent, estrogen is responsible for many aspects of brain differentiation (reviewed in Ref.1), some elements of masculinization in the guinea pig are more dependent on androgens (24). In sheep, the specific steroid action is not known, although data from the rat (25) suggest that estrogen is the key steroid in defeminizing the LH surge. Nothing is yet known about the specific steroids responsible for masculinization of tonic LH secretion in sheep. It is tempting to propose that estrogen defeminizes the LH surge while androgens masculinize tonic LH, clearly a hypothesis worthy of testing.

We are currently unsure where gonadal steroids are acting to masculinize gonadotropin secretion. A key determinant of the sex difference in the timing of puberty in sheep is the sexual differentiation of photoperiod responsiveness (4). Current work from our laboratory (10) and others (26, 27) suggests that male and female lambs have different photoperiod requirements for timing puberty. To exhibit a sustained increase in tonic LH secretion, females require the shortening days of late summer and autumn (4); males have no such light requirements and can initiate reproductive activity under a variety of photoperiods, including the increasing day lengths of spring (11, 26). Furthermore, androgenized female lambs treated with testosterone from days 30–86 of gestation have a reduced responsiveness to photoperiod cues and an advanced timing of neuroendocrine sexual maturity (10), much like males. These and other findings have led to the hypothesis that one important organizing action of prenatal androgens in sheep to modify the timing of puberty is through altering the characteristics of the photoperiod response system.

From an integration of our current and previous studies, some understanding of the sexual differentiation of gonadotropin secretion in sheep is beginning to develop. Defeminization of the LH surge mechanism is highly dependent on the duration of prenatal steroid exposure and much less so on the amount. Differentiation of the control of tonic LH secretion and the timing of its increase at puberty, however, rely on an integration of both duration and amount of prenatal steroid for masculinization. Although it is completely uncertain how and where testosterone is acting during development, the findings that different steroid requirements exist for tonic and surge modes of gonadotropin secretion suggest that the underlying neural elements may arise independently within the brain.

	Acknowledgments

 
We are grateful to Mr. Richard and Mrs. Marilyn Wallen (Hubbard Lake, MI) for providing high quality lambs for this study; Mr. Douglas D. Doop and Ms. Juanita Pelt for expert technical advice and assistance; Dr. David C. Bucholtz, Dr. Christopher L. Medina, Mr. John M. Ling, and Ms. Heather M. Patton for their help in conducting the experiment; Gary R. McCalla of the Sheep Research Core Facility for conscientious animal care; the Reproductive Sciences Program Assays and Reagents Core Facility for standardization of hormone RIA reagents; Dr. Gordon D. Niswender, Colorado State University, and Dr. Leo E. Reichert, Jr., Albany Medical College, for providing reagents used in the LH assay.

	Footnotes

 
¹ Preliminary reports of this work were presented at the 10th International Congress of Endocrinology, San Francisco, CA, 1996. This work was supported by USDA Grants 92–0269 and 93–0184, and the Office of the Vice President for Research at the University of Michigan.

² Present address: College of Medicine, Department of Obstetrics and Gynecology, Fifth Floor Means Hall, 1654 Upham Drive, Ohio State University, Columbus, Ohio 43210-1228.

Received August 5, 1996.

	References

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