Dr. Ron’s Research Review – September 7, 2011

This week’s research review focuses on FSH & LH and Vitamins C and E, Manganese and Vitex.

Vitamin E deficiency causes decreased hormone synthesis and increased secretion of pituitary LH owing to the feedback mechanism. (Akazawa, Mikami et al. 1987)

Vitamin C inhibits stimulated LHRH release by scavenging nitric oxide. (Karanth, Yu et al. 2000)

Manganese acts centrally to activate reproductive hormone secretion, and increases LH, FSH and testosterone in male rates. (Lee, Pine et al. 2006)

Manganese stimulates LHRH secretion in prepubertal female and adult male rats. (Lee, Hiney et al. 2007) (Prestifilippo, Fernandez-Solari et al. 2007) (Prestifilippo, Fernandez-Solari et al. 2008)

Vitex agnus castus extract decreased significantly LH and testosterone levels in male mice. (Nasri, Oryan et al. 2007)

An earlier study found that in vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus castus. (Jarry, Leonhardt et al. 1994)

Dr. Ron


Articles

Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats

            (Lee, Pine et al. 2006) Download

Manganese (Mn) is an important element for normal growth and reproduction. Because Mn accumulates in the hypothalamus and is capable of stimulating puberty-related hormones in female rats, we assessed whether this metal could cause similar effects in male rats. We have demonstrated that MnCl2, when administered acutely into the third ventricle of the brain, acts dose dependently to stimulate luteinizing hormone (LH) release. Furthermore, there was a dose dependent stimulation in the secretion of LH-releasing hormone (LHRH) from the medial basal hypothalamus in vitro, and administration of an LHRH receptor antagonist in vivo blocks Mn-induced LH release. To assess potential chronic effects of the metal, male pups were supplemented with 10 or 25 mg MnCl2 per kg by gastric gavage from day 15 until days 48 or 55, at which times developmental signs of spermatogenesis were assessed. Results demonstrate that while significant effects were not observed with the 10 mg/kg dose, the animals receiving the 25 mg/kg dose showed increased LH (p<0.05), FSH (p<0.01) and testosterone (p<0.01) levels at 55 days of age. Furthermore, there was a concomitant increase in both daily sperm production (p<0.05) and efficiency of spermatogenesis (p<0.05), demonstrating a Mn-induced acceleration in spermatogenesis. Our results suggest Mn is a stimulator of prepubertal LHRH/LH secretion and may facilitate the normal onset of male puberty. These data also suggest that the metal may contribute to male precocious pubertal development should an individual be exposed to low but elevated levels of Mn too early in life.

Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action

            (Lee, Hiney et al. 2007) Download

We have shown recently that Mn2+ stimulates gonadotropin secretion via an action at the hypothalamic level, and a diet supplemented with a low dose of the element is capable of advancing the time of female puberty. In this study, we used an in vitro approach to investigate the mechanism by which Mn2+ induces luteinizing hormone-releasing hormone (LHRH) secretion from prepubertal female rats. The medial basal hypothalamus from 30-day-old rats was incubated in Locke solution for 30 min to assess basal LHRH secretion, then incubated with buffer alone or buffer plus either a nitric oxide synthase (NOS) inhibitor (N-monomethyl-L-arginine (NMMA); 300 or 500 microM) or a soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ); 100 or 250 microM) for another 30 min. Finally, the incubation continued for a further 30 min, but in the presence of MnCl2 (50 or 250 microM) to assess the effect of the blockers on stimulated LHRH secretion. Both 50 and 250 microM MnCl2 stimulated LHRH release (P < 0.05 and P < 0.01, respectively). The addition of 300-500 microM NMMA to the medium did not block Mn2+-stimulated release of LHRH, even with the higher dose of MnCl2. Furthermore, while 50, 100 and 250 microM MnCl2 all significantly induced LHRH release, the two lowest doses did not stimulate total nitrite released from the same tissue, an effect only observed with the highest dose. Taken together, these data suggest that Mn2+ is not an effective stimulator of NO. Conversely, inhibiting sGC with ODQ blocked the Mn2+-stimulated secretion of LHRH in a dose-dependent manner, indicating that GC is the site of action of Mn2+. Additionally, we showed that Mn2+ stimulated cGMP and LHRH from the same tissues, and that downstream blocking of protein kinase G formation with KT5823 (10 microM) inhibited Mn2+-induced LHRH release. These data demonstrate that the principal action of Mn2+ within the hypothalamus is to activate sGC directly and/or as a cofactor with available NO, hence generating cGMP and resulting in prepubertal LHRH release.

Effect of manganese on luteinizing hormone-releasing hormone secretion in adult male rats

            (Prestifilippo, Fernandez-Solari et al. 2007) Download

Recently studies have demonstrated that low doses of (Mn(+2)) in the form of manganese chloride can stimulate specific puberty-related hormones and advance signs of pubertal development in immature female and male rats. In the present study, we used an in vitro system to evaluate the ability of 0, 50, 250, and 500 microM doses of Mn(+2) to stimulate luteinizing hormone-releasing hormone (LHRH) secretion and to assess the hypothalamic mechanism of this action in adult male Sprague-Dawley rats. We demonstrated that Mn(+2) at 500 microM, but not the lower doses, increased LHRH release, nitric oxide (NO) synthase (NOS) activity, and the content of cyclic cGMP in the medial basal hypothalamus. Inhibition of NOS with a competitive inhibitor (Nomega-nitro-L-arginine methyl ester hydrochloride) prevented the Mn-induced increase in LHRH release. Additionally, methylene blue and KT5823, specific inhibitors of guanylyl cyclase and protein kinase G (PKG), respectively, also blocked the stimulatory effect of Mn(+2) on LHRH release. These in vitro studies demonstrated that the hypothalamic mechanism of Mn(+2) action in adult males is by activation of the NOS/NO system, resulting in increases in cGMP and PKG and thus the secretion of LHRH from the nerve terminals. These results indicate Mn(+2) can cause LHRH release in adult males, and this action is discussed in relation to age, gender, as well as mechanistic and functional differences between adult and immature animals.


Acute effect of manganese on hypothalamic luteinizing hormone releasing hormone secretion in adult male rats: involvement of specific neurotransmitter systems

            (Prestifilippo, Fernandez-Solari et al. 2008) Download

Manganese chloride (MnCl2) is capable of stimulating luteinizing hormone releasing hormone (LHRH) secretion in adult male Sprague-Dawley rats through the activation of the hypothalamic nitric oxide/cyclic guanosine monophosphate (cGMP)/protein kinase G pathway. The present study aimed to determine the involvement of specific neurotransmitters involved in this action. Our results indicate that dopamine, but not glutamic acid and prostaglandins, mediates the MnCl2 stimulated secretion of LHRH from medial basal hypothalami in vitro, as well as increases the activity of nitric oxide synthase. Furthermore, a biphasic response was observed in that gamma aminobutyric acid (GABA) release was also increased, which acts to attenuate the MnCl2 action to stimulate LHRH secretion. Although it is clear that manganese (Mn+2) can acutely induce LHRH secretion in adult males, we suggest that the additional action of MnCl2 to release GABA, a LHRH inhibitor, may ultimately contribute to suppressed reproductive function observed in adult animals following exposure to high chromic levels of Mn+2.

The effects of Vitex agnus castus extract and its interaction with dopaminergic system on LH and testosterone in male mice

            (Nasri, Oryan et al. 2007) Download

The purpose of this study was to evaluate the probable effects of Vitex agnus castus (Vac.) on the male reproductive physiology. It is a well known fact that LH secretion from the anterior pituitary of mammals is controlled by many neurotransmiters such as dopamine. In this experiment, we have studied the effect of Vac. extract on the LH and testosterone hormones and its interaction with the dopaminergic system on male mice. In order to evaluate these effects, we used the hydroalcoholic Vac. extract (for extraction we used percolation technique) injection with the following doses: 65, 165, 265, 365 and 465 mg kg-', bromocriptine as a dopamine receptor agonist (5, 10, 20 mg kg(-1)) and haloperidol as a dopamine receptor antagonist (1, 1.5, 2, 2.5, 3 mg kg(-1)). To study the interaction between Vac. extract and dopaminergic system, we injected the optimum doses of Vac. with bromocriptine or haloperidol at the same time. Intraperitoneal injections were applied in all experiments, once a day for 30 days. The control group remained intact and the sham group received vehicle. After the last injection, we collected the animal blood serums for hormonal assays. LH and testosterone were measured by Radio Immuno Assay (RIA). LH and testosterone, showed significant decrease in bromocriptine group and haloperidol increased these hormones. Vac. extract decreased significantly the LH and testosterone levels. The coadministration of Vac. extract and bromocriptine decreased LH and testosterone. Coadministration of Vac. extract and haloperidol decreased LH and testosterone levels. These results suggest: dopamine regulates the gonadotroph-leydig cells axis. It appears that Vac. exertes effects through dopaminergic system and other pathways. The findings of this study show we can use Vac. extract for pathological cases of increasing LH and testosterone.


References

Akazawa, N., S. Mikami, et al. (1987). "Effects of vitamin E deficiency on the hormone secretion of the pituitary-gonadal axis of the rat." Tohoku J Exp Med 152(3): 221-9.

Jarry, H., S. Leonhardt, et al. (1994). "In vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus castus: direct evidence for a dopaminergic principle by the dopamine receptor assay." Exp Clin Endocrinol 102(6): 448-54.

Karanth, S., W. H. Yu, et al. (2000). "Ascorbic acid acts as an inhibitory transmitter in the hypothalamus to inhibit stimulated luteinizing hormone-releasing hormone release by scavenging nitric oxide." Proc Natl Acad Sci U S A 97(4): 1891-6.

Lee, B., J. K. Hiney, et al. (2007). "Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action." J Physiol 578(Pt 3): 765-72.

Lee, B., M. Pine, et al. (2006). "Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats." Reprod Toxicol 22(4): 580-5.

Nasri, S., S. Oryan, et al. (2007). "The effects of Vitex agnus castus extract and its interaction with dopaminergic system on LH and testosterone in male mice." Pak J Biol Sci 10(14): 2300-7.

Prestifilippo, J. P., J. Fernandez-Solari, et al. (2008). "Acute effect of manganese on hypothalamic luteinizing hormone releasing hormone secretion in adult male rats: involvement of specific neurotransmitter systems." Toxicol Sci 105(2): 295-302.

Prestifilippo, J. P., J. Fernandez-Solari, et al. (2007). "Effect of manganese on luteinizing hormone-releasing hormone secretion in adult male rats." Toxicol Sci 97(1): 75-80.