Paramethasone acetate (PA): corticosteroid potency vs hypothalamic pituitary-gonadal axis

Because paramethasone acetate (PA) suppresses basal and midcycle LH surge and blocks estrogen synthesis in the female, its possible effect upon testicular physiology was evaluated in 13 healthy men by measuring the circulating levels of FSH, LH, prolactin (PRL), testosterone (T), dihydrotestosterone (DHT), androstenedione (A), estradiol (E2) and cortisol (C) every 4 h throughout the day, before (control) and after PA (6 mg/d/7 d). The total concentrations of each hormone, as well as the PA-induced suppressibility (measured as percent decrease in the mean 24 h plasma level) were analyzed. PA suppressed neither the basal nor circadian rhythm of T and had no effect on LH, FSH or PRL output. DHT, A, E2 were significantly reduced and the basal concentrations and circadian variations of C were abolished. PA showed a dual control on the pituitary gonadal axis and while causing a maximal suppressed adrenocortical activity it had no interference in testosterone synthesis.     

Effects of testosterone, dihydrotestosterone and estradiol on gonadotropin release after gonadotropin releasing hormone administration in cyclic mares

Sixteen intact cyclic mares were treated on the fourth day of estrus and then every other day for a total of six injections with 1) testosterone propionate, 2) dihydrotestosterone (DHT) benzoate, 3) estradiol (E2) benzoate or 4) safflower oil. Mares were given gonadotropin releasing hormone (GnRH) on Day 3 of estrus (pretreatment) and again 24 h after the last steroid or oil injection. Treatment with testosterone propionate resulted in a greater (P less than 0.05) follicle-stimulating hormone (FSH) response to the second injection of GnRH compared with all other treatments. Treatment with DHT benzoate also resulted in greater (P less than 0.05) FSH response to GnRH compared with control and E2 benzoate-treated mares. Testosterone propionate and E2 benzoate administration suppressed (P less than 0.05) the normal diestrous rise in FSH concentrations exhibited by the control and DHT benzoate-treated mares. Steroid treatment did not affect the luteinizing hormone (LH) response to GnRH, although testosterone propionate treatment did suppress concentrations of LH in daily blood samples during Days 3 to 6 of treatment. It is concluded that testosterone's effect on FSH after GnRH treatment observed in this and previous experiments can be attributed to two different properties of the hormone or its metabolites acting simultaneously. That is, testosterone increased the secretion of FSH in response to GnRH as did DHT (an androgenic effect). At the same time, testosterone suppressed FSH concentrations in daily blood samples in a manner identical to that of E2 benzoate (an estrogenic effect).     

Effects of corticosterone on the negative feedback action of testosterone, 5 alpha-dihydrotestosterone and estradiol in the adult male rat

Corticosterone acetate (10 mg/day) was administered to gonadectomized and adrenalectomized male rats bearing 5, 10 or 15 mm long testosterone filled silicone elastomer capsules. It was found that the serum testosterone levels induced by these capsules were not influenced by corticosterone treatment and that the weights of the prostates in the corticosterone treated rats were not different from their controls. In contrast, corticosterone acetate increased markedly the LH and FSH inhibitory effects of testosterone. Since several brain structures are able to convert testosterone into 17-beta-hydroxy-5-alpha-androstan-3-one (5-alpha-dihydrotestosterone) and/or estradiol, and these metabolites are probably involved in mechanisms controlling gonadotropin secretion, we studied also the effects of corticosterone on the feedback action of dihydrotestosterone and estradiol. 5 alpha-Dihydrotestosterone was administered by 5, 10 or 20 mm long elastomere capsules whereas estradiol was given by daily s.c. injections of 0.125, 0.25 or 0.50 micrograms estradiol benzoate. In the presence of corticosterone acetate the gonadotropin inhibitory action of testosterone, 5 alpha-dihydrotestosterone and estradiol increased more than 2 times.     

Testosterone and zinc supplementation in castrated rats: Effects on plasma leptin levels and relation with LH, FSH and testosterone

The present study aims to examine how zinc and testosterone supplementation, in combination and separately, affect plasma LH, FSH and leptin levels in castrated rats. Eighty experimental animals used in the study were allocated to 8 groups, each containing an equal number of rats. Group 1, control group; Group 2, castration group; Group 3, testosterone group (5 mg/kg/day); Group 4, zinc-supplemented group (3 mg/kg/day); Group 5, testosterone and zinc-supplemented group; Group 6, zinc-supplemented castration group; Group 7, testosterone and castration group; and Group 8, zinc-supplemented, testosterone and castration group. Plasma zinc, leptin, LH, FSH and free and total testosterone levels were determined in the blood samples collected from the animals by decapitation. Group 2 had the highest leptin levels and together with group 6, it also showed the highest LH and FSH levels (p<0.01). The lowest leptin levels were observed in groups 3 and 7 (p<0.01). Leptin levels in groups 4 and 6 were higher than those in groups 1, 5 and 8 (p<0.01). LH levels in group 4 were lower than those in groups 2 and 6 and higher than those in all other groups (p<0.01). Free and total testosterone levels in groups 7 and 8 were lower than those in groups 3 and 5, but higher than those in all other groups (p<0.01). Plasma LH levels may be more effective than testosterone on plasma leptin and zinc may be an important mediator of the effect LH has on leptin.     

Effects of androgen administered to neonatal male rats on hypophyseal gonadotropin content, secretion and response to LHRH at adulthood

Supraphysiologic doses (1.75-3.50 mg) of testosterone propionate (TP) administered to male rats on the day of birth and 24 h later resulted in markedly reduced serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in adult males castrated for 16 days. These effects diminished as androgen was injected on succeeding postnatal days. Since exogenous dihydrotestosterone and testosterone were similarly effective, aromatization to estrogen is not required to elicit these effects. No build-up of either gonadotropin occurred in the pituitaries of TP-treated animals; pituitary LH content was appreciably reduced, while FSH remained unchanged. These data imply that hypophyseal synthesis and secretion of gonadotropins are curtailed in adult castrated males who have been androgenized neonatally. Pituitaries of such neonatally treated animals, however, were capable of increased secretion of LH in response to a challenge of luteinizing hormone-releasing hormone. These findings are compatible with a model in which an androgen suppressible event occurs at a suprahypophyseal level, e.g., hypothalamus or higher brain centers, in the male rat during a restricted neonatal period, which is responsible for programming the development of mechanisms involved in accumulation and secretion of gonadotropins.     

Effect of cyanoketone on follicle-stimulating hormone (FSH) induction of receptors for FSH in granulosa cells of the rat

Follicle-stimulating hormone (FSH) enhances the conversion of testosterone or androstenedione into estradiol by stimulating the aromatase enzyme system. Estradiol also enhances FSH action. Thus, a synergistic action of FSH and estradiol may be required for maturation of ovarian follicles. We hypothesized that estradiol may be required for FSH action. Thus, blocking estrogen synthesis should prevent FSH-induced increases in FSH receptors. Hypophysectomized rats were divided into five groups and injected subcutaneously with: 1) saline, 2) cyanoketone (0.05 mg, blocks the conversion of pregnenolone to progesterone), 3) ovine FSH (oFSH, 200 micrograms), 4) cyanoketone then oFSH 24 h later, or 5) cyanoketone plus estradiol [or progesterone, testosterone, promegestrone (R5020), dihydrotestosterone (DHT), 2 mg], then FSH 24 h later. Animals were decapitated at 0, 12 or 24 h after an injection of oFSH, and membrane receptors for FSH and luteinizing hormone (LH), plus nuclear receptors for estradiol from granulosa cells, were measured. LH receptor levels were increased only after administration of FSH and estradiol. At 0 and 24 h, numbers of FSH or estradiol receptors were similar in saline- and cyanoketone-treated animals. FSH alone increased (P less than 0.01) FSH and estradiol receptors 3-fold and 4-fold, respectively, over controls by 12 and 24 h. Cyanoketone prevented these increases in FSH and estradiol receptors. Estradiol replacement fully reversed the effects of cyanoketone on FSH action. Replacement with progesterone and testosterone was able to only partially restore levels of FSH receptors; however, estradiol receptor numbers were also increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal regulation of activities of 4-ene-5 beta- and 5 alpha-reductases and 17 beta-hydroxy-dehydrogenase in immature golden hamster testis

We have reported [1-3] in immature golden hamster testis that 5 beta-reductase is localized in the tubular nongerm cells, while 5 alpha-reductase is present in the interstitial tissue and that the 17 beta-hydroxy-dehydrogenase activity is found predominantly in the tubular nongerm cells. Hormonal regulation of these enzyme activities was examined in the present study. Male golden hamsters were hypophysectomized on day 22 after birth. The hypophysectomized hamsters in groups of 3-8 were injected daily with 10 micrograms NIH-LH-S19, 50 micrograms NIAMD-Rat-FSH-B-1, 8 or 16 micrograms NIAMD-oFSH-13, 8 micrograms NIAMD-oFSH-13 plus 5 or 10 micrograms NIH-LH-S19, 1 mg testosterone propionate or saline for 5 days starting from day 23. Testicular homogenates of the treated hamsters and intact hamsters on day 28 were incubated with [14C]4-androstene-3,17-dione and NADPH, and enzyme activity (nmol/testes/h) was estimated. The activities of 5 beta- and 5 alpha-reductases and 17 beta-hydroxy-dehydrogenase decreased significantly 6 days after hypophysectomy. In the hypophysectomized hamster testis, a distinct response to FSH but not to LH in the activities of 5 beta-reductase and 17 beta-hydroxy-dehydrogenase was found. The injection of LH in addition to FSH showed no significant additive effects on these enzyme activities. The 5 alpha-reductase activity was stimulated significantly by LH plus FSH but not by LH alone, FSH alone or androgen. These results show that 5 beta-reduction of 4-ene-3-ketosteroids takes place in the Sertoli cells under the influence of FSH while 5 alpha-reduction occurs in the interstitial cells under the influence of LH and FSH in immature hamster testis.     

Effect of dexamethasone on plasma concentrations of LH, FSH and testosterone in women with hirsutism.

Thirty sexually mature women with hirsutism were treated with 3 x 1.5 mg dexamethasone per day over a period of three days. Before and after treatment, plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were determined. While an effect of dexamethasone on LH plasma levels could not be established statistically, FSH and testosterone plasma concentrations decreased significantly in comparison to their initial values (p less than 0.01). Special attention is directed to the different effects of dexamethasone on LH and FSH plasma concentrations.     

Reduced intrafollicular androstenedione and estradiol levels in early-treated prenatally androgenized female rhesus monkeys receiving follicle-stimulating hormone therapy for in vitro fertilization

Five early-treated and four late-treated prenatally androgenized and five normal female rhesus monkeys were studied to determine whether prenatal testosterone propionate exposure beginning Gestational Days 40-44 (early-treated) or 100-115 (late-treated) affects follicular steroidogenesis during recombinant human FSH (rhFSH) treatment. All monkeys underwent rhFSH injections, without human chorionic gonadotropin administration, followed by oocyte retrieval. Serum FSH, LH, estradiol (E2), progesterone (P), 17alpha-hydroxyprogesterone (17 OHP), androstenedione (A4), testosterone, and dihydrotestosterone were measured basally during rhFSH therapy and at oocyte retrieval. Follicle fluid (FF) sex steroids, oocyte fertilization, and embryo development were analyzed. Circulating FSH, E2, 17 OHP, A4, and dihydrotestosterone levels increased similarly in all females. Serum LH levels decreased from basal levels in normal and late-treated prenatally androgenized females but were unchanged in early-treated prenatally androgenized females. Serum P levels at oocyte retrieval were comparable with those before FSH treatment in all females. All prenatally androgenized females showed reduced FF levels of A4 and E2 but not P or dihydrotestosterone. Intrafollicular T concentrations also were significantly lower in late-treated compared with early-treated prenatally androgenized females or normal females. In early-treated prenatally androgenized females, but not the other female groups, intrafollicular A4 and E2 levels were reduced in follicles containing oocytes that failed fertilization or produced zygotes with cleavage arrest before or at the five- to eight-cell embryo stage. Therefore, in monkeys receiving rhFSH therapy alone without human chorionic gonadotropin administration, early prenatal androgenization reduced FF concentrations of E2 and A4 in association with abnormal oocyte development, without having an effect on P, testosterone, or dihydrotestosterone concentrations.     

Hormonal secretion in male rats chronically treated with [D-Trp6, Pro9-NEt]-LRF.

Chronic daily administration of the LRF agonist [DTrp⁶, Pro⁹NEt]LRF (A) was accompanied by a blunting of the LH, FSH and testosterone responses. However, plasma LH levels continued to be elevated with each injection, while plasma FSH values remained within control range. As a result, LH/FSH ratios of treated rats were higher than those of control animals. Preinjection plasma testosterone levels were significantly lowered. Repeated injections of A were usually accompanied by increases in plasma progesterone levels which were largest on the second day of qd administration schedules. The intermittent administration of A every 2nd, 3rd or 4th day resulted in continued large increases in plasma progesterone concentrations. These results suggest that the periodically elevated secretion of progesterone and/or LH in the presence of lowered levels of circulating testosterone, may play a role in the paradoxical antigonadal effects of LRF agonists.     

Effects of luteinizing hormone on superovulatory and steroidogenic responses of rat ovaries to infusion with follicle-stimulating hormone

Immature female rats were infused s.c. continuously over a 60-h period with a partially purified porcine pituitary follicle-stimulating hormone (FSH) preparation having FSH activity 4.2 x NIH-FSH-S1 and luteinizing hormone (LH) activity 0.022 x NIH-LH-S1. High rates of superovulation were observed in rats receiving 1 U FSH/day, with 69 +/- 11 oocytes/rat recovered as cumulus-enclosed oocytes from oviducts on Day 1 (equivalent to the day of estrus). Addition of LH to the FSH, at dosages equivalent to 2.5-100 micrograms/day NIH-LH-S1 equivalents (2.5-100 mU) resulted in a dose-related inhibition of superovulation, reaching a nadir of 15 +/- 7 oocytes recovered from rats receiving 50 mU LH/day together with 1 U FSH/day. At the two highest LH doses, 50 and 100 mU/day, ovulation was advanced so that 12 +/- 3 and 15 +/- 4 oocytes, respectively, were recovered from oviducts of these rats flushed on the morning of Day 0, compared to none in rats infused with FSH alone. Ovarian steroid concentrations (ng/mg) observed on the morning of Day 0 in rats infused with FSH alone were progesterone, 0.50 +/- 0.13; testosterone, 0.16 +/- 0.08; androstenedione, 0.06; and estradiol, 0.23 +/- 0.05. On the morning of Day 1, ovarian progesterone concentrations in rats infused with FSH alone had risen to 3.30 +/- 0.33 ng/mg, whereas concentrations of testosterone, androstenedione, and estradiol, had fallen to essentially undetectable levels. Addition of LH to the FSH infusion resulted in dose-related increases, on Day 0, of all four steroids up to a dosage of 25 mU LH/day. At higher LH dosages, Day 0 ovarian concentrations of androgens and estradiol fell markedly, while progesterone concentrations continued to increase. Histological examination of ovaries revealed increases in the extent of luteinization of granulosa cells in follicles with retained oocytes on both Days 0 and 1 in rats infused with 25 and 50 mU LH/day together with 1 U FSH/day, compared to those observed in rats receiving FSH alone. These findings indicate that the elevated progesterone levels on Day 0 and inhibition of ovulation observed at these LH doses were due to premature luteinization of follicles, thus preventing ovulation. At lower LH doses, no sign (based on histologic or steroidogenic criteria) of premature luteinization was evident, suggesting that the decreased superovulation in these rats was due to decreased follicular maturation and/or increased atresia rather than to luteinization of follicles without ovulation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep

The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.     

Effects of androgens on serum concentrations of gonadotropins and ovarian steroids in gilts

To examine how androgens affect endocrine events associated with increased ovulation rate, gilts were injected with androgen receptor agonists, an antagonist, or a combination of both. Blood samples were collected hourly from Day 13 to estrus (Day 0 = onset of estrus) coincident with gilts (n = 6 per treatment) receiving daily treatments of vehicle (corn oil), 10 mg of testosterone, 10 mg of 5 alpha-dihydrotestosterone (dihydrotestosterone), 1.5 g of flutamide (an androgen receptor antagonist), testosterone plus flutamide, or dihydrotestosterone plus flutamide. Treatment of gilts with testosterone or dihydrotestosterone alone increased (P < 0.05) concentrations of FSH in serum, and these effects were blocked by cotreatment with flutamide. Estradiol-17beta and androstenedione concentrations in serum were increased (P < 0.05) at 2 h after injection of testosterone or testosterone plus flutamide but not after dihydrotestosterone treatment, probably because of the role of testosterone as a substrate for estradiol-17beta and androstenedione synthesis. There were no effects of the six treatments on serum concentrations of progesterone during luteolysis, but treating gilts with testosterone shortened (P < 0.05) the proestrous period. Total embryonic loss by Day 11 in gilts treated with dihydrotestosterone was reversed when gilts were cotreated with dihydrotestosterone plus flutamide. Results of this experiment indicated that androgen actions both increased FSH secretion and reduced embryonic survival by a mechanism(s) dependent on the androgen receptor.     

Selective failure of androgens to regulate follicle stimulating hormone beta messenger ribonucleic acid levels in the male rat

FSH beta, as well as LH beta, and alpha-subunit mRNA levels were examined in the pituitary glands of male rats after sex steroid replacement at various times (7, 28, or 90 days) after orchiectomy. Testosterone propionate, dihydrotestosterone propionate, or 17 beta-estradiol benzoate (E) were administered daily for 7 days before killing, to assess the role of different gonadal steroids on gonadotropin subunit mRNA levels. Subunit mRNAs were determined by blot hybridization using rat FSH beta genomic DNA, and alpha and LH beta cDNAs. At all time points, alpha and LH beta mRNAs increased after gonadectomy and fell toward normal levels with either androgen or estrogen replacement. FSH beta mRNA levels increased variably postcastration: 4-fold at 7 days, 2-fold at 28 days, and 4- to 5-fold at 90 days. Although E replacement uniformly suppressed FSH beta mRNAs, neither testosterone propionate nor dihydrotestosterone propionate administration suppressed FSH beta mRNA levels at any time point after orchiectomy. These data demonstrate that there is a relative lack of negative regulation of FSH beta mRNA levels by androgens in a paradigm in which E administration results in marked negative regulation of FSH beta mRNA levels. Thus, in the male rat, estrogens negatively regulate all three gonadotropin subunit mRNA levels while androgens negative regulate LH beta and alpha-subunit but fail to suppress FSH beta mRNAs.     

The effect of FSH on LH induced testosterone secretion in the immature hypophysectomized male rat

The effect of gonadotropin pretreatment of hypophysectomized male rats on LH stimulated serum testosterone concentrations was studied. A 5 day pretreatment period began 2 days after hypophysectomy at 21 or 24 days of age. On the day following the pretreatment period the animals received an intraperitoneal injection of saline or LH 60 min before blood collection. Animals pretreated with NIH-FSH-B1, or with doses of LH approximating the amount present in the NIH-FSH, had increased testosterone concentrations after LH stimulation compared to similarly stimulated saline pretreated animals. Pretreatment with more highly purified FSH Ex 199C at a lower dose than the minimum effective dose of NIH-FSH was also effective. There was no synergistic or additive effect when FSH Ex 199C and LH pretreatments were combined. FSH Ex 199C is more potent and contains appreciably less LH contamination than NIH-FSH-B1. The results obtained using FSH Ex 199C indicate that FSH, independent of LH contamination, can increase testes response to LH stimulation.     

Estradiol-17 beta and androgen secretion by isolated porcine ovarian follicular cells in vitro

The cellular sources and gonadotropic regulation of porcine ovarian estrogen and androgen were assessed by culturing isolated granulosa cells and thecal cells from medium size follicles (4-6 mm diameter) separately for 24 h in a chemically defined medium containing gonadotropins and (or) testosterone. At the end of the culture period, estradiol-17 beta (estradiol) and androgens in the media were determined by radioimmunoassays. Production of estradiol by granulosa cells without an exogenous aromatizable androgen was low in the absence or presence of a highly purified preparation of either follicle-stimulating hormone (FSH. 0.25 microgram/mL) or luteinizing hormone (LH. 1 microgram/mL). Addition of testosterone or androstenedione (0.5 microM), but not dihydrotestosterone or pregnenolone, significantly increased estradiol secretion. Additional increases were observed when FSH, LH, prostaglandin E2, or dibutyryl cyclic 3'.5'-adenosine monophosphate was present. Production of estradiol by thecal cells was low in the presence or absence of exogenous testosterone, and was essentially unaffected by the presence of gonadotropins. Thecal cells, however, released large amounts of androstenedione and smaller amounts of testosterone and other androgens during 24-h culture and the production of these androgens was stimulated by LH but not by FSH. Androgen secretion by granulosa cells was negligible when compared with the theca and was unaffected by gonadotropins. It is concluded that the theca is the prime site for follicular androgen biosynthesis by the porcine ovarian follicle, and, upon LH stimulation, may provide androgen precursors for estradiol production by granulosa cells.     

A new male hypogonadism mutant rat (hgn/hgn): concentrations of testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in the serum and the responsiveness of accessory sex organs to exogenous T, FSH, human chorionic gonadotropin, and luteinizing hormone-releasing hormone

To determine the etiology of male hypogonadism in a newly found mutant rat (hgn/hgn, with a single autosomal recessive trait), concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured, and the responsiveness of the urogenital organs, hypothalamus, and pituitary gland to testosterone (1 mg/kg s.c. for 7 days), FSH (0.3 AU/kg s.c. for 7 days), human chorionic gonadotropin (hCG) (40 IU/kg s.c. for 7 days), and luteinizing hormone-releasing hormone (LHRH) (0.5 or 5.0 micrograms/kg s.c. for 7 days) were tested. Treatment with testosterone only increased the weights of all of the accessory sex organs, whereas treatment with FSH, hCG, or LHRH did not. Levels of serum FSH and LH were extremely higher and testosterone was lower in hgn/hgn males than in normal males. Serum FSH and LH decreased to levels found in intact animals after treatment with testosterone, suggesting that hypothalamic responsiveness to exogenous testosterone is present in the hgn/hgn males. Thus, the status of the hgn/hgn males was indicated to be due to primary Leydig cell dysfunction.     

Unilateral ovariectomy, flutamide treatment and HCG reverse the anovulatory action of antiprogesterone RU486 in rat.

Administration of antiprogesterone RU486 (4 mg/day) from estrus through proestrus to cyclic rats blocked ovulation. Moreover, RU486 increased basal serum concentrations of LH, PRL, testosterone and estradiol, while it decreased basal serum concentration of FSH. Both unilateral ovariectomy and antiandrogen flutamide treatment, as well as an ovulatory injection of HCG in the proestrus afternoon partially reversed, the ovulatory blockade of RU486. These results indicate that both the decreased FSH concentration and the increased testosterone concentration, as well as the reduced ovulatory LH release are responsible for the anovulatory effects of RU486.     

Blockade of pulsatile LH, FSH and testosterone secretion in rams by constant infusion of an LHRH agonist

Adult Soay rams were infused for 21 days with 50 micrograms buserelin/day, using s.c. implanted osmotic mini-pumps. The continuous treatment with this LHRH agonist induced a supraphysiological increase in the blood concentrations of LH (15-fold) and testosterone (5-fold) followed by a decrease below pre-treatment values after 10 days. The blood concentrations of FSH showed only a minimal initial increase but the subsequent decrease was dramatic, occurring within 1 day. By Day 10 of treatment, the blood concentrations of all 3 hormones were low or declining, LH pulses were absent in the serial profiles based on 20-min blood samples and the administration of LHRH antiserum failed to affect the secretion of LH or testosterone. By Day 21, the secretion of FSH, LH and testosterone was maximally suppressed. The i.v. injection of 400 ng LHRH was totally ineffective at stimulating an increase in the blood concentrations of LH while the i.v. injection of 50 micrograms ovine LH induced a normal increase in the concentrations of testosterone; this confirmed that the chronic treatment with the LHRH agonist had desensitized the pituitary gonadotrophs without markedly affecting the responsiveness of the testicular Leydig cells. The ratio of bioactive: radioimmunoactive LH did not change during the treatment. The long-term effect of the infusion was fully reversible as shown by the increase in the blood concentrations of FSH, LH and testosterone and the return of normal pulsatile fluctuations in LH and testosterone within 7 days of the end of treatment.     

Prenatal Exposure to Androgen Excess Increases LH Pulse Amplitude During Postnatal Life in Male Sheep

Prenatal exposure to excess testosterone has a profound impact on reproductive and metabolic functions in young and adult female sheep. Nevertheless, few studies have addressed the impact of prenatal exposure to an excess of androgens on reproductive and metabolic functions in males. The aim of the present study was to assess the impact of prenatal exposure to an excess of testosterone or dihydrotestosterone on the luteinizing hormone (LH) pulse characteristics during sexual development in male sheep. Control male sheep (C-males) and males born to mothers exposed to twice weekly injections of 30 mg testosterone or dihydrotestosterone from day 30-90 and 40 mg from day 90-120 of gestation (T-males, DHT-males) were studied at 5, 10, and 20 weeks of age, ages that represent infancy, early prepubertal, and late prepubertal stages of sexual development in this species, respectively. Patterns of LH pulsatility showed that T- and DHT-males exhibited a higher secretion of LH during the 6-h study and a higher amplitude of the LH pulses compared with C-males. Moreover, nadir of the pulses was higher in T- and DHT-males compared with C-males. Frequency of LH pulses, however, was not different within ages or between groups. These results show that males can be responsive to prenatal androgenization and suggest that treatment transiently alters the amplitude of LH pulses probably as the result of defects in the pituitary responsiveness pattern or in the gonadotropin-releasing hormone (GnRH) release pattern.