Increased Plasma Follicle-stimulating Hormone Research Articles

Evidence for Leydig Cell Dysfunction in Infertile Men with a Selective Increase in Plasma Follicle-Stimulating Hormone*

Recent studies in acutely castrated males of several species have demonstrated that testosterone (T) alone, given in doses that produce normal plasma T levels, can maintain normal plasma FSH and LH levels. This suggests that a nonsteroidal factor from the seminiferous tubule is not required to regulate FSH release, and raises the possibility that Leydig cell function may not be fully normal in oligo- or azoospermic men with increased plasma FSH levels. To clarify this, we studied T production rates in 11 sexually mature, infertile, but otherwise healthy men who had increased plasma FSH and normal plasma LH, T, and estradiol levels and in 9 normal men. Although individual plasma T and LH levels in the infertile men were within the normal ranges, the mean plasma T level of the infertile men was significantly lower (P less than 0.002), and the mean plasma LH level was significantly higher (P less than 0.002) than values in the normal men. The infertile men also had significantly lower plasma free T concentrations (P less than 0.005), while sex hormone-binding globulin and estradiol levels were similar to those of the normal men. The production rate of T in the infertile men was half that in the normal men (P less than 0.001). We conclude that T production is significantly reduced in infertile men who have a selective increase in plasma FSH. Because of the known role of Leydig cell sex steroids in the negative feedback control of FSH, this finding may explain the elevated plasma FSH concentrations characteristic of men with germ cell loss without the need to postulate a deficiency of a separate seminiferous tubule factor.

Inhibin-mediated feedback control of follicle-stimulating hormone secretion in the female rat.

The secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland is regulated by the interaction of hypothalamic and gonadal hormones. Recently, proteins termed inhibins that selectively suppress FSH secretion have been purified and characterized from the gonadal fluids of several species. Antibodies to a synthetic peptide encompassing the amino terminal 25 residues of the recently characterized porcine inhibin were used to develop a specific radioimmunoassay (RIA) for inhibin and to neutralize endogenous inhibin during the estrous cycle of the rat. The administration of 20 international units of pregnant mare serum gonadotropin (PMSG) stimulated the secretion of inhibin in intact immature female rats, whereas ovariectomy caused an abrupt decrease in plasma inhibin concentrations that were not prevented by the injection of PMSG. The infusion of a polyclonal antiserum to inhibin, from 12 noon on proestrus to 1 a.m. on the morning of estrus, as well as its acute intravenous injection during diestrus I or II, caused an increase in plasma FSH (but not luteinizing hormone) concentrations. These results support the hypothesis of a feedback loop between the release of ovarian inhibin and FSH in the female rat.

Postcastration rise in plasma gonadotropins is blocked by a luteinizing hormone-releasing hormone antagonist.

The dependence of the acute increases in plasma gonadotropins following castration on luteinizing hormone-releasing hormone (LHRH) was assessed with the use of a potent LHRH antagonist [ALHRH; (Nac-L-Ala1,p-Cl-D-Phe2,D-Trp3,6) LHRH]. Blood samples were collected from male and female rats at the time of castration and 2, 4, 8, 12, 24 and 48 h following and plasma gonadotropin levels were determined. Immediately following castration (diestrus I for females) animals received one of the following treatments: females-vehicle, 100 micrograms ALHRH, 50 micrograms estrogen benzoate (EB), or 100 micrograms ALHRH + 50 micrograms EB; males-vehicle, 100 micrograms ALHRH, 500 micrograms testosterone propionate (TP), or 100 micrograms ALHRH + 500 micrograms TP. ALHRH blocked the selective increase in plasma follicle-stimulating hormone (FSH) observed in female rats as well as the parallel increases in both gonadotropins seen in male rats following castration. Administration of EB or ALHRH + EB to females significantly suppressed both gonadotropins compared with control levels. However, EB alone did not completely block the rise in plasma FSH in females. In males, all three treatments significantly suppressed the increases in both gonadotropins when compared with control levels. These data demonstrate that hypothalamic LHRH plays an essential role in the acute elevations of plasma gonadotropins following castration in rats. In addition, these data suggest that the selective rise of FSH in females is dependent on LHRH stimulation of pituitary gonadotropes.

Increased ovulation rate of adult ewes treated with anti-bovine LH antiserum during the normal breeding season.

Adult Suffolk ewes (n = 14) were treated on d 10 of the estrous cycle with anti-bovine luteinizing hormone (LH) antiserum. Control ewes (n = 10) were treated with normal horse serum. Estrous behavior and the number of corpora lutea and ovarian follicles were examined at the subsequent estrous cycle. Daily plasma concentrations of progesterone (P4), follicle stimulating hormone (FSH) and estradiol were determined before and after treatment. Ewes treated with antiserum had a higher (P less than .05) ovulation rate (2.7 +/- .2) than did controls (2.1 +/- .1). No differences were found in the numbers of large (greater than 5 mm) or small (less than 5 mm) follicles between treatment groups. Estrus was delayed (P less than .025) approximately .6 d/in ewes treated with antisera. Immunoreactive FSH increased (P less than .05) within 1 d after treatment and remained higher than the controls for 5 d. Peak estradiol concentrations occurred on d 17 for treated ewes compared with peak concentrations on d 15 or 16 for control ewes. The P4 concentrations were generally less (P less than .025) in treated ewes throughout the luteal phase of the treatment cycle. These data demonstrate that ovulation rate is increased in ewes treated with LH antiserum. The marked increase in plasma FSH suggests a possible mechanism whereby ovulation rate is enhanced.

Effect of gonadotropin-releasing hormone, stage of sexual maturation and 6-methoxybenzoxazolinone on plasma gonadotropins, ovarian development and uterine weight in prepuberal gilts

Two experiments were conducted with prepuberal gilts at 60, 120 and 160 days of age to a) determine the effect of 6-methoxybenzoxazolinone 6-MBOA) on reproductive plasma hormone concentrations and organ development, and b) determine how plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations before and after injection of gonadotropin-releasing hormone (GnRH) or 6-MBOA varied in relation to ovarian development. In Exp. 1, 12 gilts were used in a 4×4 Latin square design. Four gilts/age group were injected once with: 1) vehicle, 2.5% propylene glycol in 50% ethanol, 2) 2 μg of GnRH/kg body weight (BW), 3) 0.2 mg of 6-MBOA/kg BW, and 4) 2 mg of 6-MBOA/kg BW on four successive days in random order. Blood was collected via indwelling vena cava catheters. Injection of GnRH into gilts increased plasma FSH and LH at each age compared with vehicle (P<0.05). Hormone profiles for FSH and LH differed among age groups (P<0.01), but area under curves did not differ significantly among age groups. Injection of 6-MBOA did not significantly affect plasma FSH and LH. Plasma FSH and LH before the GnRH injection or on days when GnRH was not injected were greater at 60 than at 120 and 160 days (FSH, 128 vs 54 and 42 ng/ml; LH, 0.38 vs 0.16 and 0.13 ng/ml for 60, 120 and 160 days, respectively (P<0.05). In Exp. 2, vehicle, 0.2 or 2 mg of 6-MBOA/kg BW were injected once daily for 7 days in 19 gilts. Injections of 6-MBOA had no detectable effects on gonadotropin secretion, ovarian development or uterine weight. Between 60 and 120 days of age, vesicular follicles developed, ovarian weight increased 20-fold, and uterine weight increased 10-fold (P<0.05); basal concentrations of plasma FSH and LH decreased three- and twofold, respectively.

The prostaglandin inhibitor effect of antiinflammatory drugs in the therapy of male infertility

The effects of various doses of indomethacin and ketoprofen as compared with placebo were examined in 100 oligospermic patients who participated in this study. It was found that the treatment increased sperm count, sperm motility, and fertilizing capacity. The radioimmunoassay examination showed an increase in plasma follicle-stimulating hormone and luteinizing hormone but a decrease in testosterone. The results show that the influence of indomethacin was better in the dose of 75 mg daily. The mechanism of those changes is not clear. Treatment should be at least 60 days.

Effects of gonadectomy and sex steroids on pituitary gonadotrophin release and response to gonadotrophin-releasing hormone (GnRH) agonist in the bullfrog, Rana catesbeiana

Gonadectomy of adult bullfrogs, Rana catesbeiana, elevated plasma levels of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Profiles of plasma gonadotrophins after gonadectomy were similar in the two sexes; however, FSH increased faster in females than males. Both gonadotrophins continued to rise for several months and remained elevated after 1 year, but there was some dissociation between the two hormones; FSH increased sooner (1 week vs 3 weeks), reached higher levels ( FSH LH ⪢ 1 ), and did not show the secondary decline exhibited in LH. Similarly, in subadult males and females, gonadectomy increased plasma FSH by 1 week but LH levels were less affected. Postgonadectomy increases in both gonadotrophins were prevented by chronic (6-week) implantation of capsules containing estradiol-17β (E 2) or 5α-dihydrotestosterone (DHT), and treatment with DHT and E 2 within physiological ranges starting 1 year after gonadectomy also suppressed chronically elevated levels of plasma gonadotrophins. Compared to untreated gonadectomized frogs, the rate of increase in both plasma gonadotrophins was accelerated after removal of DHT at 6 weeks. Acute pituitary responsiveness to a gonadotrophin-releasing hormone (GnRH) agonist was markedly reduced in short-term (3.5–8 weeks) gonadectomized subadult males (but not females) and in long-term (1 year) gonadectomized males and females. Treatment with E 2 had no effect on GnRH responsiveness in these frogs, but DHT implants significantly enhanced the response to agonist in both sexes. Thus, the nonaromatizable androgen—DHT—may have both negative feedback effects (at the hypothalamic level) and positive effects at the level of the pituitary, whereas, estrogen exhibited only the former, negative feedback activity. Sex differences in circulating DHT, which are detectable even in juveniles, may account for the sexual dimorphism in pituitary responsiveness to GnRH in the bullfrog.

Effect of beta-adrenergic drugs on LH, FSH, and growth hormone (GH) secretion in conscious, ovariectomized rats.

The effects of third ventricular (3V) injection of the beta-adrenergic antagonist, propranolol (PROPR), a selective beta 1-antagonist, metoprolol (MET), a selective beta 2-antagonist, IPS 339, and a beta-adrenergic agonist (-) isoproterenol (ISOPR), on plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and growth hormone (GH) were studied in conscious, ovariectomized (OVX) rats. Samples were removed from unrestrained rats which had been previously implanted with atrial and 3V cannulae, and plasma hormone levels were determined by radioimmunoassay (RIA). Intraventricular injection of PROPR (30 micrograms), MET (40 micrograms), or IPS 339 (20 micrograms) induced a gradual elevation in plasma GH concentrations, whereas ISOPR (30 micrograms) reduced plasma GH. ISOPR (30 micrograms) brought about a decrease in plasma LH concentrations, but PROPR, MET and IPS 339 had no effect on LH levels. PROPR (30 micrograms) increased plasma FSH concentrations, but there was no significant effect of MET, IPS 339 or ISOPR on FSH secretion. The results indicate that the beta-adrenergic system can inhibit the release of GH, LH, and FSH. This system appears to have a tonic inhibitory effect on GH and FSH but not LH release in the OVX rat.

Pituitary and gonadal responses to continuous infusion of gonadotropin releasing hormone in the male bullfrog, Rana catesbeiana.

Results of continuous constant-rate intravenous infusions of synthetic mammalian gonadotropin releasing hormone (GnRH) for 1–4 days into intact adult male bullfrogs, Rana catesbeiana, indicate that the control and dynamics of gonadotropin [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] secretion in the frog differs from that in mammals. In the bullfrog, there was no temporal dissociation between the secretory profiles of the two gonadotropins (Gn), and the pituitary did not develop a clear refractoriness to GnRH even after 3–4 days of continuous infusion. A dose-response relationship was observed both for the temporal pattern and magnitude of increase in plasma Gn during infusion. For the two frogs at the lowest dose of GnRH (0.25 μg/h), increases in plasma FSH and LH were gradual. At all higher doses, a biphasic pattern of increase in both plasma FSH and LH was apparent; this consisted of an initial peak in plasma Gn at 0.5–1.0 h and a second higher peak at about 24 h (n=5) or 48 h (n=1) of infusion. Thereafter, levels of plasma Gn remained relatively stable and elevated well above baseline (by at least 50× and 20× for LH and FSH, respectively) for the duration of infusion. The highest levels of plasma Gn were attained during the course of infusion with 8.0 μg/h GnRH; the responses to 1.0 and 4.0 μg/h were lower and indistinguishable from one another and 0.25 μg/h GnRH was only marginally effective in elevating plasma Gn. Associated with changes in plasma Gn were concomitant increments in plasma androgen that usually peaked at 2–5 h (n=4) or about 24 h (n=4), and, like plasma Gn, remained elevated above pretreatment levels for the duration of each infusion. Thus, the intact male bullfrog is unlike most male or female mammals tested in lacking a pronounced pituitary (or gonadal) desensitization for up to 4 days of continuous GnRH infusion.

The relationship of plasma gonadotropins and androgen concentrations to body growth in boys.

Abstract. Plasma concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17 alpha-hydroxyprogesterone (17α-OPH), androstenedione (Δ4) and testosterone (T) were measured in 543 healthy boys aged 6.0 to 15.9 years (with weight and height between the 3rd and 97th percentile for Mexican standards) as a function of chronologic age (CA), weight, height, surface area (SA) and calculated lean body mass (LBM) and total body fat (TBF). The earliest hormonal event was a clear rise in plasma 17α-OHP, either prior or simultaneously to at steady increase in plasma FSH, far ahead of any sign of puberty. These changes were closely followed by a continuous rise in plasma Δ4. Thereafter, there was a prolonged period of low but progressively increasing plasma FSH levels in the face of constantly low LH levels. However, a brisk rise in plasma LH and FSH occurred at a mean weight of 35.4 kg, at a height of 144.5 cm and when LBM was 32.0 kg. Simultaneously, plasma 17α-OHP began to fall, Δ4 reached a plateau and soon after, a marked rise in plasma T was documented. When plasma LH and FSH concentrations were plotted against CA, weight, height, SA and LBM a significant quadratic equation was disclosed in each case. Both gonadotrophins did not correlate with TBF. Multiple variance analysis demonstrated that LBM and SA had the most marked effect on LH, while LBM was the most important variable affecting plasma FSH concentrations. The present data suggest the association between a "critical level" of body composition and the major hormonal events in boys, regardless of a cause-effect relationship. A critical level of LBM (20–23 kg) and not of TBF was attained at time of the initial hormonal changes, as well as at the time of the major changes in plasma gonadotrophins (32–35 kg).

Development of a homologous radioimmunoassay for ovine follicle stimulating hormone: studies after estrus, ovariectomy, estradiol and releasing hormone.

The development of a specific, sensitive homologous ovine follicle stimulating hormone (FSH) radioimmunoassay (RIA) is described. The key procedural modifications of basic RIA methods were immunoabsorption of the anti-ovine FSH serum with lutenizing hormone (LH) to improve specificity and adsorption chromatography of the radioiodinated ovine FSH on hydroxyapatite (HTP) to improve immunoreactivity. Cross-reactivity of the immunoabsorbed FSH antisera (R5-4IA) was less than .5% with NIH-prolactin-S10, NIH-GH-S11, NIH-TSH-S5 and LER-LH-1374a. Sensitivity (5.5 ng of NIH-FSH-S10) of the assay was adequate for quantification of plasma FSH in all ewes studied. Accuracy of the assay was high. The recovery of FSH from ovine plasma was nearly quantitative (y = −5.5 + 1.1X, r2 .999), and the mean ratio of biological potency by bioassay to immunological potency by RIA of several FSH preparations was 1 ± .2. Intraassay and interassay coefficients of variation were both less than 15%. Four studies with Rambouillet ewes were conducted. Study 1 was with ovariectomized ewes. FSH and LH both increased at a similar rate after surgery. Values for both hormones were four- to sixfold greater 15 days after surgery than before surgery. Study 2 was with ewes at estrous. Two peaks of similar magnitude were observed in plasma FSH. The first occurred about 10 hr after the onset of estrus and coincided with the large peak in plasma LH. The second occurred about 24 hr later, when plasma LH was low. Study 3 was with ovariectomized ewes that were injected with estradiol. Plasma concentration of both FSH and LH tended to decline for the first 6 hr postinjection. The large peak in plasma LH, which occurred about 14 hr postinjection, was similar in both height and duration to that observed in estrous ewes. The small increase in plasma FSH, which coincided with the LH peak, was not significant. Study 4 was conducted with ovariectomized ewes given single or multiple injections of LH-RH/FSH-RH. Both FSH and LH increased significantly, but the response was considerably greater for LH. These results confirm that the anti-ovine FSH serum after immunoabsorption and radioiodinated ovine FSH after absorption chromatography on HTP were reliable reagents for the development of a specific, sensitive homologous ovine FSH radioimmunoassay.

Possible existence of a long-loop feedback system between FSH and inhibin in female rats.

Experiments were designed in which peripheral plasma inhibin levels were presumably altered in an attempt to investigate an interdependency between pituitary follicle-stimulating hormone (FSH) and ovarian inhibin secretion. In the first study, unilateral ovariectomy (ULO) was performed on 4-day cycling female rats under ether anesthesia at 0800 h on diestrous day 1 (D1). Inhibin-like activity [FSH-inhibiting activity(FSH-IA)] in untreated ovarian venous plasma (OVP) collected from the remaining ovary was assessed by an in vitro pituitary bioassay system. Both plasma FSH levels and FSH-IA significantly increased between 4 and 12 h after ULO. Thereafter, plasma FSH declined between 12 and 32 h after ULO, whereas FSH-IA remained elevated during this same time interval. Compared to sham-operated rats, plasma FSH was significantly elevated 4, 12, and 24 h after ULO, whereas FSH-IA was statistically higher only at 32 h after ULO. In a second experiment, rats were injected with charcoal-treated porcine follicular fluid (PFF) on proestrus and estrus. Control rats received saline. The data indicate that increased plasma FSH levels on D1 in PFF-treated rats (FSH rebound) may be a consequence of reduced endogenous inhibin secretion on estrus. As well, return of FSH to control levels on D2 in PFF-treated rats may have resulted from an FSH-associated increase in FSH-IA on D1 and D2.

Growth Inhibition of Estrogen-Sensitive Rat Mammary Tumors. Effect of an Alpha-Fetoprotein-Secreting Hepatoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

The growth and regression patterns of estrogen (E)-sensitive mammary tumors (SNMU) and autonomous mammary tumors (ANMU) were studied in normal, castrated, and alpha-fetoprotein (AFP)-secreting and nonsecreting hepatoma-bearing female BUF rats. Both SNMU and ANMU tumors had comparable amounts of E receptor. SNMU tumors grew faster in female hosts than in male hosts. The latency period of SNMU tumors was lengthened when the tumor was inoculated into newborn hosts. These E-sensitive tumors regressed after castration of the adult hosts. Tumor regression was also observed in SNMU-bearing rats inoculated with AFP-secreting hepatomas. The growth pattern of the ANMU tumor was not affected by the sex or age of the host. Castration and inoculation of hepatomas to ANMU tumor-bearing rats did not result in regression of the ANMU tumors. We suggest that AFP inhibited the growth of E-sensitive cells in newborn and hepatoma 7777-bearing hosts. This inhibitory effect of AFP could not be attributed to a "functional castration" resulting from the trapping of 17 beta-estradiol (E2) by AFP, because the plasma levels of E2 in these animals affect levels of gonadotropins. Moreover, castration of hepatoma 7777-bearing rats resulted in increased plasma follicle-stimulating hormone and luteinizing hormones levels. The results strongly suggested that a) the malignant properties of E2-sensitive cells in adult hosts can be controlled by AFP, and b) the mechanism by which AFP inhibits the growth of E2-sensitive cells is independent of the E2 "trapping" phenomenon. An ontogenetic approach to the mechanism of action of estrogens may account for available results.

Effect of electrical stimulation of the hypothalamus on gonadotrophin release and the onset of puberty.

SUMMARY Electrical stimulation of the hypothalamus with biphasic pulses was performed in immature female rats. When performed at 27 days of age or later, electrical stimulation in the arcuate nucleus region advanced puberty in all animals, as did stimulation of the anterior hypothalamus at 29 days of age or later. Stimulation in younger rats did not uniformly advance puberty. The responsiveness to electrical stimulation thus seems to develop a few days earlier in the arcuate nucleus region than in the anterior hypothalamus. In a second experiment the possible involvement of follicle-stimulating hormone (FSH) in the advancement of puberty was investigated: the simplified augmented ovarian weight assay for endogenous FSH was performed in rats stimulated in the arcuate nucleus region as well as in controls. A marked increase in ovarian weight, indicating increased FSH levels, was demonstrated in all animals stimulated on day 27 or later; at earlier ages only a percentage of the stimulated animals responded. This percentage paralleled the percentage of animals that showed advancement of puberty. It is concluded that electrical stimulation in both the arcuate nucleus region and the anterior hypothalamus advances the onset of puberty. It is suggested that electrical stimulation causes increased plasma FSH levels and, in consequence, precocious puberty.

Studies of the pituitary-Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia: comparison with normal men, prepuberal boys, and hypopituitary patients.

Pituitary and gonadal function was studied in seven chromatin-negative men, ages 15-27 yr, with retarded sexual and somatic development, skeletal anomalies, and hyposmia. These hyposmic patients were compared with normal men, prepuberal boys and hypogonadal patients with hypopituitarism. The urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels of hyposmic subjects were the same as those of normal boys and hypopituitary patients but significantly lower than those of normal men. Clomiphene citrate did not cause an increase in plasma FSH and LH levels in either hypogonadal group as it does in normal men. In contrast to hypopituitary patients, thyroid and adrenocortical function and release of growth hormone in the hyposmic subjects were normal. The plasma testosterone levels were equally low in prepuberal, hypopituitary, and hyposmic patients but were increased to a greater extent by human chorionic gonadotropin (HCG) treatment in prepuberal and hypopituitary subjects than in the hyposmic patients. Prolonged treatment with HCG has failed to return plasma testosterone levels to normal in two hyposmic patients. These observations suggest that there are defects of both pituitary and Leydig cell function in men with the syndrome of hypogonadism, skeletal anomalies, and hyposmia. They have impaired secretion of FSH and LH and a Leydig cell insensitivity to gonadotropin.