Showing papers on "Testosterone published in 1986"

A Physiological Role of Epidermal Growth Factor in Male Reproductive Function

Abstract: Epidermal growth factor (EGF) stimulates the proliferation of various mammalian cells in culture, but its physiological role is not well defined. In mature male mice, large amounts of EGF are produced in the submandibular gland; it is present in the circulation at approximately 5 nanograms of EGF per milliliter of plasma. Sialoadenectomy (removal of the submandibular glands) decreased the amount of circulating EGF to an undetectable level but did not affect the circulating levels of testosterone or follicle-stimulating hormone. The number of mature sperm in the epididymis decreased by as much as 55 percent; the number of spermatids in the testis decreased by 40 to 50 percent; and the number of spermatocytes increased by about 20 percent. Administration of EGF to sialoadenectomized mice restored both the sperm content of the epididymis and the number of spermatids in the testis to normal. Thus, EGF may play a role in male reproductive function by stimulating the meiotic phase of spermatogenesis.

Stimulation of cell proliferation and estrogenic response by adrenal C19-delta 5-steroids in the ZR-75-1 human breast cancer cell line.

Abstract: We have examined the effect of androst-5-ene-3β,17β-diol (Δ5-diol) and its precursors, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3β-sulfate (DHEAS), on the growth of the estrogen-sensitive human breast cancer cell line, ZR-75-1. While the cell number was increased up to 4-fold by maximal concentrations of estradiol, Δ5-diol maximally stimulated cell proliferation by approximately 3-fold. Since the half-maximal stimulation achieved by Δ5-diol is observed at 2.5 nm and the normal range of plasma concentrations of this steroid in women is 1 to 3 nm, it is most likely that the stimulatory effect of Δ5-diol has physiological significance. DHEA and DHEAS were much less effective than Δ5-diol in stimulating the proliferation of ZR-75-1 cells, the maximal effect on cell number being 75% at the maximal dose used, namely 10 µm. The mitogenic effects of estradiol and Δ5-diol were competitively inhibited by the antiestrogen LY156758 (keoxifene), while the effects of DHEA and DHEAS were completely abolished by the antiestrogen. The effects of DHEA and Δ5-diol on cell proliferation are not likely to be mediated via their conversion to estrone or estradiol, since androstenedione had no effect, while testosterone and dihydrotestosterone decreased cell number by about 20%. The number of specific progesterone binding sites was increased 3.7-, 3.2-, and 2.0-fold by Δ5-diol, DHEA, and DHEAS, respectively. The relative potency of the C19-Δ5-steroids to increase the number of progesterone-specific binding sites was comparable to their ability to stimulate cell proliferation. Direct competition experiments performed with intact cells in monolayer culture showed that, under conditions of minimal metabolism, only Δ5-diol could significantly compete with estradiol for cellular estrogen-specific binding sites with an apparent dissociation constant of 11 nm, thus suggesting that physiological concentrations of C19-Δ5-steroids of adrenal origin could exert an estrogenic stimulation of breast tumor growth without involvement of the aromatase pathway. The present data suggest not only that estrone derived from androstenedione could play a role in estrogensensitive breast cancer in women but that Δ5-diol could well be the most important estrogen in breast cancer in women.

Treatment of Prostate Cancer with Gonadotropin-Releasing Hormone Agonists

Abstract: It is now well established that chronic treatment with GnRH agonists offers an advantageous alternative to orchiectomy and estrogens for the treatment of prostate cancer. Castration levels of androgens can thus be easily achieved without side effects other than those related to castration levels of serum androgens. However, man is unique among species in having a high secretion rate of precursor adrenal steroids which are converted into active androgens in the normal prostate and prostatic cancer. All the enzymes required for the transformation of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and androst-5-ene-3 beta, 17 beta-diol are present in prostatic tissue. Moreover, as shown in many systems, castration levels of serum testosterone (T) at 0.2-0.4 ng/ml exert significant androgenic activity in target tissues. In order to inhibit the action of androgens of both testicular and adrenal origin, GnRH agonists have been administered in association with the pure antiandrogen Flutamide in patients having clinical stage D2 (bone metastases) prostate cancer. A positive objective response assessed according to the criteria of the United States National Prostatic Cancer Project (USNPCP) has been observed in 84 of the 88 patients who had received no previous treatment (95.4%). After 2 yr of treatment, the probability of continuing response is 70% compared to 0-10% by previous approaches. In addition, the death rate at 2 yr is at 10.9% as compared to approximately 50% after standard hormonal therapy. When the same treatment was applied to patients who had received previous hormonal therapy (orchiectomy, estrogens or GnRH agonists alone) before showing a relapse, the response rate decreased to 62.9% and the death rate at 2 yr was 52%.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of selective destruction and regeneration of rat Leydig cells on the intratesticular distribution of testosterone and morphology of the seminiferous epithelium.

Abstract: This study was designed to explore the relationship between the intratesticular distribution of testosterone and spermatogenesis by completely destroying the Leydig cells of mature male rats with injection of a single i.p. dose of ethane dimethanesulphonate. After such treatment, testosterone levels in serum, testicular interstitial fluid, seminiferous tubules, and whole testis declined significantly 6 to 24 hours after injection and fell below assay detection limits between 3 and 7 days. At 3 and 7 days, serum LH and FSH levels rose significantly and remained elevated up to 4 and 6 weeks, respectively, in comparison with vehicle-treated controls. Leydig cells disappeared from the interstitium by day 3, but between 2 and 4 weeks postinjection a new generation of fetal-like Leydig cells repopulated the testicular interstitium and, during weeks 6 to 10, were transformed into, or replaced by, Leydig cells with an adult type of morphology. Histologic examination of the seminiferous tubules showed progressive disruption of spermatogenesis between 3 and 14 days post-ethane dimethanesulphonate. The first histologic sign of spermatogenic damage was noted at day 3, with the occurrence of stage-specific degenerating pachytene primary spermatocytes at stages VII to VIII of the spermatogenic cycle. On day 7, these cells and degenerating round, or step 19, spermatids often were observed during stages VII to XI, although qualitatively normal spermatogenesis also was seen in these and all other stages of the cycle. Maximum impairment of spermatogenesis occurred 2 weeks post-ethane dimethane sulphonate, at which time the tubules commonly lacked one or more germ cell generations or, alternatively, showed accumulation of lipid inclusions, extracellular spaces, and variable numbers of degenerating germ cells. Following repopulation of the testis by Leydig cells during weeks 3 and 4, spermatogenesis recovered. By 10 weeks after treatment, qualitatively normal spermatogenesis was seen in the great majority of seminiferous tubules, although a few tubules still remained in which the germ cell complement was severely reduced, and contained only Sertoli cells and spermatogonia.(ABSTRACT TRUNCATED AT 400 WORDS)

Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals

Abstract: The effects of exogenously administered testosterone were evaluated in a group of 19 female to male transsexuals who underwent bilateral salpingo-oophorectomy after a variable period of androgen therapy. The findings were compared to those in an age-matched group of 12 patients who underwent pelvic surgery for nonendocrine reasons. The most significant finding in the 19 androgen-treated female transsexuals was the finding of enlarged or borderline enlarged ovaries in 5 subjects. In addition, we found 1) multiple cystic follicles in 17 patients (89.5%), 2) diffuse ovarian stromal hyperplasia in 16 patients (84.2%), 3) collagenization of the outer cortex in 13 patients, and 4) luteinization of stromal cells in 5 patients (26.3%). Findings consistent with polycystic ovaries were thus present in 13 of the 19 patients based on the presence of 3 of the above 4 findings. The data suggest that increased blood levels and presumably increased ovarian concentrations of testosterone may produce the morphological feat...

Reproductive hormone increases in response to acute exercise in men.

Abstract: The increase in serum testosterone levels generally observed with intense, short-term exercise remains unexplained since most investigators have not reported any increase in the levels of luteinizing hormone, the pituitary glycoprotein most responsible for testicular steroidogenesis. Hemoconcentration and decreased metabolic clearance have been suggested as mechanisms to explain the exercise-associated testosterone increase. Such non-specific mechanisms should apply to other steroid hormones as well as to testosterone. To investigate whether the exercise-induced changes in other steroid hormones were similar to that of testosterone, we measured serum levels of testosterone, androstenedione, dehydroepiandrosterone, and cortisol as well as gonadotropins, luteinizing hormone and follicle-stimulating hormone, and prolactin at 5-15 min intervals throughout progressive maximal intensity exercise on a cycle ergometer. Significant increases were observed with all hormones with exercise. The increase in serum testosterone began prior to exercise, peaked at 20 min after the beginning of exercise, and fell to baseline within 10 min. The serum luteinizing hormone increase was synchronous with that of testosterone, suggesting that gonadotropin stimulation was not responsible for the testosterone increment. The increments in serum cortisol, androstenedione, dehydroepiandrosterone, and prolactin levels were simultaneous but began 25-30 min after that of testosterone in all subjects. These findings, therefore, suggest that, contrary to previous evidence, the exercise-associated increase in serum testosterone results predominantly from a specific mechanism, presumably involving increased testicular production without gonadotropin stimulation.

Ethylene dimethanesulfonate destroys Leydig cells in the rat testis.

Abstract: Ultrastructural changes in the interstitial cells of the adult rat testis were studied up to 45 days after administration of a single dose (100 mg/kg) of the antifertility compound ethylene dimethanesulfonate (EDS). Most Leydig cells showed degenerative changes 12 h after treatment. Twenty-four and 48 h after injection, all Leydig cells observed showed gross degenerative changes. At 4 and 14 days, intact Leydig cells could not be identified in the interstitial spaces. Twenty-one days after treatment with EDS, small Leydig cells were visible, and at 45 days, Leydig cells appeared normal. The seminiferous epithelium appeared morphologically normal until 4 days after injection of EDS, when slight abnormalities were observed. At 14 and 21 days, the seminiferous epithelium was grossly abnormal, but at 48 days, spermatogenesis appeared normal. Twelve, 24, and 48 h after treatment, large quantities of material, presumably from dead Leydig cells, were observed within the macrophage cytoplasm. The predominant cell in the interstitial space 4 and 14 days after EDS was the macrophage. Inclusions from the dead Leydig cells within the cytoplasm of the macrophages had almost disappeared. LH receptors (hCG binding) in testicular homogenates were consistent with the cytological changes in Leydig cells. Receptor concentration was low at 24 h and was almost zero at 4 days. This change was accompanied by a decrease in serum testosterone to castrate levels by 2 days. The responses of the endocrine system to destruction of the Leydig cell by EDS, as monitored by serum FSH, LH, and testosterone, were slower than those after castration, indicating that the response to EDS reflects the time required to kill the Leydig cell rather than direct impairment of the steroidogenic pathway. These experiments demonstrate that Leydig cells can be specifically destroyed by a cytotoxic drug. The availability of a specific cytotoxic agent for Leydig cells offers further opportunities to study the interrelationships between the Leydig cell and the seminiferous tubule.

Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche.

Abstract: To determine the adrenal contribution to elevated plasma androgens in 31 young hyperandrogenemic women with acne and/or hirsutism, we compared their responses to ACTH with those of 14 normal women. Each subject was given a low dose (10 μg/m2) of synthetic ACTH-(l–24) (Cortrosyn) after administration of 1.5 mg dexamethasone the night before the test. Thirty and 60 min responses of plasma 17α-hydroxy-pregnenolone (17-Preg), 17α-hydroxyprogesterone, (17-prog), dehydroepiandrosterone (DHEA), androstenedione, 11-deoxycortisol, and cortisol were measured. Eighteen (58%) patients had increased responses of at least one 17-ketosteroid or adrenal androgen precursor. All patients had cortisol responses within the range of those of the 14 normal subjects. Nine patients (29%) had evidence of steroid biosynthetic enzyme deficiencies, either mild congenital adrenal hyperplasia or the heterozygote state; after ACTH, 4 of these patients had elevated 17-prog in the range of values in heterozygote carriers of 21-hydroxylas...

The effects of ethylene dimethane sulphonate (EDS) on rat Leydig cells: evidence to support a connective tissue origin of Leydig cells.

Abstract: Ethylene dimetbane sulpbonate (DS) administered to adult male rats in a single dose of 75 mg/kg body weight results in a rapid destruction of Leydig cells which, in turn, is associated with a marked decline in levels of serum testosterone. For 24-72 h after treatment with EDS (post-EDS) the Leydig cells undergo degenerative changes consisting of chromatin condensation and cytoplasmic vacuolation, and testicular macrophages progressively remove Leydig cells from the intertubular tissue by phagocytosis. This results in the total absence of Leydig cells on Days 7-14 and the absence of any detectable specific ‘251-bCG binding to testis homogenates. Associated with the low levels of serum testosterone, levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum rise, LH to levels found in castrate rats. Morphometric and ‘251-bCG binding studies indicate that a new generation of Leydig cells develop from Day 21 and reach control levels by Day 49. Morphologic observations suggest that the Leydig cells arise by differentiation from a pool of connective tissue cells that includes fibroblasts, lymphatic endothelial cells and pericytes. The new Leydig cells, which appear around Day 21 post-EDS, have the features of fetal Leydig cells. The latter appear to transform into Leydig cells typical of normal adult rats between 35-49 days post-EDS. The differentiation of new Leydig cells is associated with a reestablishment of normal levels of testosterone 21 days post-EDS. Serum LH and FSH return to normal at 28 days and 49 days respectively.

Decreased Hypothalamic Gonadotropin-Releasing Hormone Secretion in Male Marathon Runners

Abstract: Hypogonadotropic hypogonadism due to a deficiency in hypothalamic gonadotropin-releasing hormone is common in female athletes ("hypothalamic amenorrhea"). It is not known, however, whether a similar phenomenon occurs in male athletes. We investigated the integrity of the hypothalamic-pituitary-gonadal axis in six highly trained male marathon runners (who were running 125 to 200 km per week). The mean (+/- SEM) frequency of spontaneous luteinizing hormone pulses was diminished in the runners, as compared with healthy controls (2.2 +/- 0.48 vs. 3.6 +/- 0.24 pulses per eight hours, P less than 0.05). The amplitude of the pulses was also low in the runners (0.9 +/- 0.24 vs. 1.6 +/- 0.15 mlU per milliliter; P less than 0.05), and the responses of luteinizing hormone to gradually increasing doses of exogenous gonadotropin-releasing hormone were decreased. Plasma testosterone levels were similar in the two groups and increased equally in response to an intramuscular injection of 2000 units of human chorionic gonadotropin. During short-term intense physical exercise (a treadmill run at 72 percent of maximal oxygen consumption for two hours), the plasma gonadotropin levels in the athletes remained stable, but significant elevations in plasma levels of cortisol, prolactin, and testosterone occurred. We conclude that highly trained male athletes, like their female counterparts, may have a deficiency of hypothalamic gonadotropin-releasing hormone. This condition may be caused by the prolonged, repetitive elevations of gonadal steroids and other hormones known to suppress gonadotropin-releasing hormone secretion that are elicited by their daily exercise.

Elevated testosterone levels during nonbreeding-season territoriality in a fall-breeding lizard, Sceloporus jarrovi.

Abstract: In many vertebrates, seasonal activation of sexual and territorial behaviors coincides with seasonal gonadal activation and is caused by the increase in sex steroid hormones. Both male and femaleSceloporus jarrovi are territorial, but in this species territorial behavior is seasonally activated in late April, months before seasonal gonadal maturation, which occurs in August prior to the fall mating season. Measurements of seasonal changes in circulating levels of the sex steroid hormones testosterone, progesterone, and estradiol indicated that testosterone levels in both sexes are elevated when territorial behavior is expressed, even during the period of nonbreeding-season territoriality during the summer. This suggests that a nonbreeding season behavior is activated by a sex steroid hormone in this species.

Effects of Steroid Hormones and Antisteroids on Alkaline Phosphatase Activity in Human Endometrial Cancer Cells (Ishikawa Line)

Abstract: Alkaline phosphatase activity in human endometrial cancer cells of the estrogen-responsive Ishikawa line was markedly stimulated (3-20-fold in 4 days) by estrogens, 5 alpha-dihydrotestosterone, and dehydroepiandrosterone but not by testosterone, medroxyprogesterone acetate, glucocorticoids, several peptide hormones, prostaglandins, or growth factors. Maximum responses to estradiol were obtained at concentrations between 10(-9) and 10(-7) M; at 10(-8) M estradiol, the highest activity was reached 48-72 h after addition of the hormone. A linear relationship between enzyme activity at 48 h and the length of exposure to the hormone was observed. Dibutyryl cyclic guanosine 3':5'-monophosphate, but not dibutyryl cyclic adenosine 3':5'-monophosphate enhanced alkaline phosphatase activity and acted synergistically with estradiol. trans-4-Monohydroxytamoxifen completely antagonized the stimulatory effect of estradiol and had no agonistic activity. Dihydrotestosterone and dehydroepiandrosterone appear to exert their effects, at least in part, by interacting with estrogen receptors, since the simultaneous presence in the medium of monohydroxytamoxifen abolished their influence on alkaline phosphatase activity. The specific antiandrogen monohydroxyflutamide partially antagonized the effect of these hormones, suggesting that their action involved androgenic mechanisms as well. Exposure to elevated temperature and to specific inhibitors identified alkaline phosphatase of Ishikawa cells as a placental-type isoenzyme, thus contrasting with the nonplacental type found in glandular epithelial cells of normal endometrium and in another human endometrial cancer cell line, HEC-50. This study extends our previous observations of estrogen responsiveness in the Ishikawa cell line. In addition to the previously reported stimulatory effects on growth and progesterone receptor levels, we are now describing the stimulation by estrogens and C19 steroids of an enzyme, alkaline phosphatase, which can be used as a convenient end point to examine mechanisms of hormonal action.

Physical and hormonal evaluation of transsexual patients: a longitudinal study.

Abstract: The physical and hormonal characteristics of 60 male-to-female transsexuals and 30 female-to-male transsexuals were measured before or during treatment with commonly used forms and dosages of hormones. Only two patients (both female-to-male) had either a congenital defect in hormonal production or abnormal genital development. Patients were seen at 3- to 6-month intervals for an average of 18 months. The response to therapy was examined over time; physical parameters, hormonal concentrations, liver function tests, lipids, and glucose were measured. Three patients were changed from ethinyl estradiol to conjugated estrogen because of liver enzyme elevations. Ethinyl estradiol (0.1–0.5 mg/day) was equal to conjugated estrogen (7.5–10 mg/day) in its ability to suppress testosterone and gonadotropins and to promote breast growth. Maximum breast growth required 2 years of therapy. During treatment with testosterone, female-to-male transsexuals had a significant mild elevation of cholesterol and triglyceride. The female-to-male transsexuals receiving testosterone cypionate, 200 mg every 2 weeks, ceased to have menstrual periods and became progressively masculinized. A mean maximal clitoral length of 4.6 cm which achieved by 1 year of therapy. Based on the data generated by this study, we recommend as hormonal therapy 0.1–0.5 mg/day of ethinyl estradiol or 7.5–10 mg/day of conjugated estrogen for male-to-female transsexuals, and intramuscular testosterone cypionate, 200 mg every 2 weeks, for female-to-male transsexuals.

17β-Estradiol 2- and 4-Hydroxylation Catalyzed by Rat Hepatic Cytochrome P-450: Roles of Individual Forms, Inductive Effects, Developmental Patterns, and Alterations by Gonadectomy and Hormone Replacement*

Abstract: The participation of rat hepatic P-450 in the conversion of 17β-estradiol to catechol estrogens was examined by means of enzyme reconstitution and immunoinhibition studies. It was thus demonstrated that three rat liver microsomal cytochrome P-450 forms, designated P-450UT-A, P-450PCN-E, and P-450ISF-G, each contribute to the 2- and 4-hydroxylation of 17β-estradiol catalyzed by hepatic microsomal preparations. Two of these enzymes, P-450UT-A and P-450PCN-E, are expressed constitutively, are male-specific, and are regulated by testosterone as well as influenced by the administration of various chemicals. Consistent with these observations, 17β-estradiol 2- and 4-hydroxylation activities both increased rapidly during puberty in male rats and were induced by treatment of rats with phenobarbital or pregnenolone 16α-carbonitrile. Castration of male rats at birth or at 5 weeks of age suppressed the levels of 17β-estradiol 2- and 4-hydroxylase activities measured at 10 weeks of age. This suppression of activity w...

Hormonal therapy of cryptorchidism. A randomized, double-blind study comparing human chorionic gonadotropin and gonadotropin-releasing hormone.

Abstract: We conducted a randomized, double-blind study comparing intranasal gonadotropin-releasing hormone (1.2 mg per day for 28 days) with parenteral human chorionic gonadotropin (3300 IU per week for four weeks) in the treatment of cryptorchidism in 33 boys one to five years old (29 with unilateral and 4 with bilateral cryptorchidism). Testicular descent into the scrotum occurred in 3 of the 16 patients (19 percent) treated with gonadotropin-releasing hormone and in 1 of the 17 (6 percent) treated with human chorionic gonadotropin (P = 0.23). The mean luteinizing hormone and testosterone levels were similar in both groups before treatment. During treatment, the testosterone levels were significantly increased in both groups, but higher levels occurred in the group treated with human chorionic gonadotropin (P less than 0.05). In a parallel (but uncontrolled) study of five boys with retractile testes (defined as a nonscrotal testis that could be manipulated into the bottom of the scrotum) who were originally excluded from the main protocol but were treated with the same regimen of human chorionic gonadotropin, descent into the scrotum occurred in all patients. We conclude that hormonal therapy with either gonadotropin-releasing hormone or human chorionic gonadotropin is, in most cases, ineffective in promoting testicular descent of true cryptorchid testes. However, short-term treatment with human chorionic gonadotropin is very effective in producing descent of retractile testes. These results suggest that the wide discrepancies in apparent efficacy in previous trials of hormonal therapy of cryptorchidism may have been due to inclusion in those studies of various proportions of patients with retractile testes.

Effects of testosterone, estradiol, and temperature on neurons in preoptic tissue slices.

Abstract: Thermosensitive preoptic neurons have been implicated in the regulation of body temperature. Testosterone- and estrogen-sensitive preoptic neurons have been implicated in reproductive behavioral and endocrine responses. In this study, rat preoptic tissue slices were used to examine the specificity of these neurons by determining their individual firing rate responses to both temperature and reproductive steroids. Of the 180 neurons classified according to thermosensitivity, 37% were warm sensitive, 8% were cold sensitive, and 55% were temperature insensitive. Ninety-three neurons were tested for their responses to perfusion media containing either testosterone or estradiol (30 pg/ml). Of the cells tested with both steroids, testosterone or estradiol affected half of the thermosensitive neurons and one-third of the temperature-insensitive neurons. This indicates that the population of temperature-insensitive neurons does not contain the majority of the steroid-sensitive neurons. There was much specificity, however, between the two types of steroid-sensitive neurons; testosterone and estradiol rarely affected the same neuron. Although these findings do not indicate a strong specificity between thermosensitive and steroid-sensitive neurons, they do support previous studies suggesting interactions between thermoregulatory and reproductive systems.

Regulation of rat luteinizing hormone subunit messenger ribonucleic acids by gonadal steroid hormones.

Abstract: Little is known about the hormonal regulation of luteinizing hormone (LH) biosynthesis We have studied the regulation of LH messenger RNA (mRNA) levels by gonadal-steroid hormones in the rat In one set of experiments, male and female rats were surgically gonadectomized (GDX) and killed 1, 3, 7, 14, 22, and 31 d postoperatively In another set of experiments, male and female rats were surgically GDX and were injected subcutaneously with testosterone propionate (500 micrograms/100 g body wt per d) or 17 beta-estradiol 3-benzoate (10 micrograms/100 g body wt per d), respectively, beginning 3 wk postoperatively Levels of serum LH were determined by radioimmunoassay and levels of LH subunit mRNAs in single pituitary glands were determined by blot hybridization analysis using labeled synthetic oligodeoxyribonucleotide probes that correspond to portions of the coding regions of the rat alpha- and LH beta-subunit mRNAs 4 wk after gonadectomy, serum LH levels rose nine- and 20-fold, while alpha-subunit mRNA levels rose six- and 10-fold, and LH beta-subunit levels rose seven- and 14-fold, compared with controls in males and females, respectively In gonadal-steroid hormone-treated male and female GDX rats, serum LH levels fell to 8 and 36% of control values, while alpha-subunit mRNA levels declined to 22 and 19%, and LH beta-subunit mRNA levels declined to 6 and 10% of control values, 48 h after injections were initiated, in males and females, respectively We conclude that gonadal-steroid hormones negatively regulate the levels of both subunit mRNAs in GDX rats in a pattern that parallels the changes in serum LH values These data suggest that gonadal-steroid hormone regulation of LH biosynthesis occurs, at least in part, at the level of LH subunit mRNAs due to effects at the transcriptional and/or RNA stability levels

Synergism between granulosa and theca-interstitial cells in estrogen biosynthesis by gonadotropin-treated rat ovaries: studies on the two-cell, two-gonadotropin hypothesis using steroid antisera.

Abstract: In mammalian ovaries, luteinizing hormone (LH) induces androgen biosynthesis by theca interna cells, whereas both follicle-stimulating hormone (FSH) and LH stimulate aromatase activity by granulosa cells. The joint action of these two types of cell and pituitary hormones forms the basis of a 2-cell, 2-gonadotropin hypothesis for biosynthesis of estrogen. We tested the synergism between these cell types using antisera against the estrogen precursors progesterone and testosterone. Ovaries were obtained from immature rats two days after a single injection of pregnant mare serum gonadotropin (PMSG). Granulosa cells were obtained by puncturing the follicles, and ovarian remnants were dissociated with collagenase to derive cells from the theca interstitium. Granulosa and theca interstitial cells were cultured alone or in combination for 20 h. Granulosa cells secreted negligible amounts of estrogen and testosterone, but contained high aromatase activity. Treatment with both FSH and human chorionic gonadotropin (hCG) increased production of progesterone in granulosa cells. In contrast, theca interstitial cells had negligible aromatase activity. Treatment with hCG, but not FSH, increased androgen production by theca interstitium; the hCG action was further augmented by the inclusion of exogenous progesterone. Furthermore, co-culture of gonadotropin-treated granulosa and theca interstitial cells resulted in substantial increases in estrogen production, indicating synergism between the two types of cell. The increases in estrogen production in the co-cultures were accompanied by decreases in progesterone content. To test the possibility that progesterone released by granulosa cells may serve as a substrate for production of androgen in theca cells, specific antiserum was used to adsorb progesterone present in the medium. Addition of the progesterone antibody inhibited gonadotropin-stimulated production of testosterone (39% decrease) and estrogen (64% decrease) by the combined cell cultures. The inhibitory effect on estrogen production could be reversed by the addition of progesterone (10(-6) M) or testosterone (10(-6) M) but not by the addition of a synthetic progestin, R5020. Since testosterone released from theca cells may serve as the substrate for aromatases in granulosa cells, specific testosterone antiserum was also used. Production of estrogens by the combined cell cultures was inhibited (78%) by the testosterone antiserum, but the inhibitory effect was completely reversed by exogenous testosterone or progesterone. Thus, synergistic interactions between granulosa and theca interstitial cells are important in effecting maximal estrogen biosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitating genetic and nongenetic factors that determine plasma sex steroid variation in normal male twins

Abstract: We have observed that familial factors have a decided influence on the plasma content of sex steroids in men both in the general population and in men of families with prostatic cancer. The contribution of genetic and nongenetic familial factors on the variation of plasma sex steroid content and action has now been investigated in 75 pairs of normal male monozygotic (MZ) twins and 88 pairs of dizygotic (DZ) twins. Zygosity was determined by measuring ten blood proteins and enzymes. The mean plasma values for testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1), and 3α-androstanediol glucuronide (3α-diol G), free T, LH, FSH, SHBG, age, and degree of adiposity were all similar between the groups of twins. Familial factors (P < 0.01) accounted for 50% or more of the variation in plasma hormone levels in MZ twins (3α-diol G, 84%; TDHT, 70%; T, 63%; E1, 63%; free T, 61%; E2, 57%; DHT, 56%; LH, 55%; and FSH, 54%) except for SHBG, which was 30%. The familial influence was greater in MZ twins than in DZ twins for all measurements except for SHBG. The heritability of the variation of hormone levels in plasma was determined from the equation: 2[rMZ(intraclass correlation) - rDZ]. Genes regulate 25% to 76% of the total variation of plasma content of the hormones except for DHT (12%) and SHBG (<1%). Genetic regulation of tissue DHT formation was suggested by observing a 48% genetic effect on the plasma content of 3α-diol G. These observations suggest that genetic factors make major contributions in regulating estrogen and testosterone levels and tissue DHT production in normal men.