Douglas L. Foster

The neural basis of puberty and adolescence

The pubertal transition to adulthood involves both gonadal and behavioral maturation. A developmental clock, along with permissive signals that provide information on somatic growth, energy balance and season, time the awakening of gonadotropin releasing hormone (GnRH) neurons at the onset of puberty. High-frequency GnRH release results from disinhibition and activation of GnRH neurons at puberty onset, leading to gametogenesis and an increase in gonadal steroid hormone secretion. Steroid hormones, in turn, both remodel and activate neural circuits during adolescent brain development, leading to the development of sexual salience of sensory stimuli, sexual motivation, and expression of copulatory behaviors in specific social contexts. These influences of hormones on reproductive behavior depend in part on changes in the adolescent brain that occur independently of gonadal maturation. Reproductive maturity is therefore the product of developmentally timed, brain-driven and recurrent interactions between steroid hormones and the adolescent nervous system.

Neuroendocrine basis of seasonal reproduction

Publisher Summary This chapter discusses the strategy of seasonal breeding, the role of photoperiod in timing the annual reproductive cycle, the hypothalamo-pituitary mechanisms that mediate photoperiodic regulation of estrous cyclicity, and the photoperiodic pathway to luteinizing hormone (LH) pulse generator. To understand how photic input to the LH pulse generator leads to seasonal changes in gonadal activity, the sequence of endocrine events that normally leads to ovulation during the estrous cycle of the ewe must be considered. These preovulatory events occur during a 2–3 day follicular phase and include a precipitous drop in progesterone, a progressive rise in tonic LH secretion, a sustained increase in estradiol secretion, and the LH surge. The pivotal step in this sequence is the sustained increase in tonic LH secretion. A great deal of insight has been gained into the complex interplay between the neural and endocrine response systems that underlie the seasonal reproductive process in the short-day breeding ewe. Specifically, light cues activate retinal photoreceptors and are transmitted via a monosynaptic tract to the suprachiasmatic nuclei of the hypothalamus. After interacting with the circadian system, the photic information is relayed to the pineal gland that transduces the neural message into a hormonal signal in the form of a circadian rhythm of melatonin secretion. The pattern of this melatonin signal, which is interpreted as inductive or suppressive, sets the frequency of the LH pulse generator and determines the capacity of this neural oscillator to respond to the negative feedback action of estradiol. The resulting changes in the episodic pattern of gonadotropin secretion, in turn, dictate whether or not estrous cycles can occur.

Evidence for GnRH Regulation by Leptin: Leptin Administration Prevents Reduced Pulsatile LH Secretion during Fasting

Administration of leptin during undernutrition improves reproductive function, but whether this occurs at the level of the brain, pituitary, or gonads is not yet clear. The present study tested the hypothesis that one important mechanism is the control of pulsatile gonadotropin-releasing hormone (GnRH) secretion. Our approach was to determine if leptin could prevent the marked suppression of pulsatile luteinizing hormone (LH) secretion which occurs during fasting. Leptin (3 µg/g i.p.; three times/48 h) or vehicle was administered during a 48-hour fast in adult ovariectomized and estrogen-treated ovariectomized rats (n = 5–7/group). LH was measured in blood samples collected every 6 min for 2 h before and after fasting. In vehicle-treated animals, plasma insulin and leptin levels decreased after fasting. As expected, the LH pulse frequency also decreased markedly. When circulating leptin remained artificially elevated during fasting, the suppression of LH pulse frequency did not occur. Leptin treatment maintained a high LH pulse frequency in the presence or absence of estrogen. The finding that leptin modulates LH pulse frequency indicates that this fat-derived hormone conveys information about nutrition to mechanisms which regulate pulsatile gonadotropin-releasing hormone secretion. Because this occurs in the absence of estrogen, the mechanism does not necessarily involve modulation of negative feedback.

Localization of Glucokinase-Like Immunoreactivity in the Rat Lower Brain Stem: For Possible Location of Brain Glucose-Sensing Mechanisms

Pancreatic glucokinase (GK) is considered an important element of the glucose-sensing unit in pancreatic β-cells. It is possible that the brain uses similar glucose-sensing units, and we employed GK immunohistochemistry and confocal microscopy to examine the anatomical distribution of GK-like immunoreactivities in the rat brain. We found strong GK-like immunoreactivities in the ependymocytes, endothelial cells, and many serotonergic neurons. In the ependymocytes, the GK-like immunoreactivity was located in the cytoplasmic area, but not in the nucleus. The GK-positive ependymocytes were found to have glucose transporter-2 (GLUT2)-like immunoreactivities on the cilia. In addition, the ependymocytes had GLUT1-like immunoreactivity on the cilia and GLUT4-like immunoreactivity densely in the cytoplasmic area and slightly in the plasma membrane. In serotonergic neurons, GK-like immunoreactivity was found in the cytoplasm and their processes. The present results raise the possibility that these GK-like immunopos...

Intra-follicular activin availability is altered in prenatally-androgenized lambs.

Prenatal exposure of sheep to testosterone (T) disrupts ovarian cyclicity and leads to anovulation in adulthood. We propose that the disruption of ovarian function in prenatally-androgenized sheep is mediated via follicular defects stemming from reduced intrafollicular activin availability/action. The intra-follicular activin availability/action that facilitates follicular development is dictated by the relative proportions of activins, inhibins (antagonists of activin action) and follistatins (FS; binding proteins of activin and negator of activin action). Inhibin alpha, beta A, beta B, and FS mRNA expression were determined by in situ hybridization in 5 week-old ovaries from control (C) lambs or those exposed to testosterone (T) or DHT from 30-90 days of gestation. In utero exposure to T, but not DHT, increased total ovarian weight (0.4+/-0.1,1.5+/-0.5 and 0.3+/-0.1 g, C, T and DHT, respectively) and total number of follicles (16.5+/-2.8,37.8+/-7.9, and 18.8+/-3.0). With the exception of two follicles in T animals, all follicles were < or = 2 mm in diameter. All follicles < or = 2 mm in all groups expressed FSH receptor mRNA in the granulosa cells and LH receptor only in the thecal cells. The percentage of follicles expressing FS mRNA was increased (P<0.05) in sheep prenatally-androgenized with either T (80.4+/-8) or DHT (80.3+/-5.5) as compared to C (50.8+/-8.2). In contrast, the percentage of follicles expressing activin beta B mRNA tended to be lower (P=0.06) in the T (30.9+/-7.1) and DHT (40.5+/-3.3) groups as compared to C (66.1+/-15.6). Increased expression of FS along with the reduced expression of activin beta B mRNA provides evidence for compromised intra-follicular activin availability in the majority of follicles in the androgenized groups. The increase in ovarian weight and follicular number in the T, but not in the DHT group, suggests that the effects of T are mediated through the action of estrogen. We speculate that the decrease in relative abundance of activin may contribute to the selection defects in prenatally-androgenized sheep. If true, this may be a useful model to understand the etiology of polycystic ovarian syndrome.

Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female.

Findings discussed in this review stress the importance of normal estrogen and androgen signaling at appropriate developmental time points in maintaining normal phenotypic expression, reproductive and metabolic function and document how inappropriate steroid signaling, at inopportune times can have undesirable outcomes. For example, inappropriate testosterone exposure during fetal life alters the developmental trajectory of the female culminating in a suite of disorders, which include intrauterine growth-retardation and postnatal catch up growth, phenotypic masculinization, reproductive neuroendocrine and ovarian disruptions leading to progressive loss of cyclicity and metabolic disruptions manifested as hyperinsulinemia.

Fetal Programming: Prenatal Androgen Disrupts Positive Feedback Actions of Estradiol but Does Not Affect Timing of Puberty in Female Sheep

Abstract We studied the impact of prenatal androgen exposure on the timing of onset of puberty, maintenance of cyclicity in the first breeding season, and the LH surge mechanism in female sheep. Pregnant sheep were injected with testosterone propionate (100 mg i.m.) twice each week from Day 30 to Day 90 (D30–90) or from Day 60 to Day 90 (D60–90) of gestation (term = 147 days). Concentrations of plasma progesterone and gonadotropins were measured in blood samples collected twice each week from control (n = 10), D60–90 (n = 13), and D30–90 (n = 3) animals. Rate of weight gain and initiation of estrous behavior were also monitored. After the first breeding season, when the animals entered anestrus, competency of the gonadotropin surge system to respond to estradiol positive feedback was tested in the absence or presence of progesterone priming for 12 days. Prenatally androgenized females had similar body weight gain and achieved puberty (start of first progestogenic cycle) at the same time as controls. Duration of the breeding season and the number of cycles that occurred during the first breeding season were similar between control and prenatally androgenized sheep. In contrast, prenatal exposure to androgens compromised the positive feedback effects of estradiol. Onset of LH/FSH surges following the estradiol stimulus was delayed in both groups of androgenized ewes compared with the controls in both the absence and presence of progesterone priming. In addition, the magnitude of LH and FSH surges in the two animals that surged in the D30–90 group were only one third and one half, respectively, of the magnitudes observed in the control and D60–90 groups. The present findings indicate that disruption of the surge system can account for the fertility problems that occur during adulthood in prenatally androgenized sheep.

Central inhibition of gonadotropin-releasing hormone secretion in the growth-restricted hypogonadotropic female sheep.

Growth retardation induced by dietary restriction results in hypogonadotropism, and thus, puberty is delayed. The present studies determined 1) whether reduced LH secretion in the growth-retarded condition is due to a reduction in the frequency and/or in the amplitude of GnRH secretion, and 2) whether the mechanism regulating LH secretion is being actively inhibited via central mechanisms. To determine whether GnRH pulse frequency and/or amplitude are reduced during growth restriction, blood samples were simultaneously collected from pituitary portal blood for GnRH and from jugular blood for LH determinations over a 4-h period in ovariectomized lambs (52 wk of age) that were either growth restricted (28 kg; n = 8) or growing normally (60 kg; n = 7). As expected, the growth-restricted females were hypogonadotropic and exhibited a long LH interpulse interval compared with the normally growing females. However, although the GnRH interpulse interval was longer in the growth-restricted lambs compared with that...

Determinants of Puberty in a Seasonal Breeder

Publisher Summary This chapter focuses on the determinants of puberty in a seasonal breeder. The evolution of seasonal breeding, natures contraceptive influences the time when fertility is first attained in the young female. Puberty occurs only during the breeding season. Thus, not only must the developing seasonal breeder be able to determine when she is sufficiently mature to begin reproductive cycles, she must also be able to determine when during the year onset of fertility will produce young during the spring and summer. The production of high-frequency luteinizing hormone (LH) pulses is clearly the pivotal force driving the transition into adulthood in the lamb. Therefore, further understanding of the timing of sexual maturation in this seasonal breeder depends upon ones ability to unravel how developmental and environmental signals modify the activity of the system generating pulsatile LH secretion by the pituitary. Based upon the work conducted in the adult and the patterns of LH observed in the lamb, there is little reason to suspect that the pubertal increase in LH pulse frequency in the young female sheep reflects anything other than an increase in frequency of the gonadotropin-releasing hormone (GnRH) pulse generator. The pubertal increase in LH pulses is occasioned by a lessening of negative feedback control of the GnRH pulse generator. The common neuroendocrine feature underlying the onset of puberty and the onset of the breeding season is the increase in GnRH pulse generator activity.

Intracerebroventricular Administration of Melanin-Concentrating Hormone Suppresses Pulsatile Luteinizing Hormone Release in the Female Rat

Melanin‐concentrating hormone (MCH) has been reported to be involved in the regulation of feeding behaviour in rats and mice. Because many neuropeptides that influence ingestive behaviour also regulate reproductive function, the present study was designed to determine if central administration of MCH changes pulsatile secretion of luteinizing hormone (LH) in the rats. Wistar‐Imamichi strain female rats were ovariectomized and implanted with oestradiol to produce a moderate inhibitory feedback effect on LH release. The effects of i.c.v. injections of MCH on LH release were examined in freely moving animals. Blood samples were collected every 6 min for 3 h through an indwelling cannula. After 1 h of sampling, MCH (0.1, 1 or 10 μg/animal) or vehicle (saline) was injected into the third cerebroventricle. Because MCH is also reported to affect the hypothalamo‐pituitary‐adrenal (HPA) axis, which in turn, can influence reproductive function, plasma corticosterone concentrations were determined in the same animals at 30‐min intervals during the first and last hours and every 12 min during the second hour of the 3‐h sampling period. When expressed as per cent changes, mean plasma LH concentrations after MCH administration were significantly lower in the animals injected with all doses of the peptide compared with vehicle‐treated animals; LH pulse frequency was significantly lowered by 1 μg of MCH. Per cent changes in mean plasma corticosterone levels were not significantly affected by MCH administration. These results in oestradiol‐treated ovariectomized rats indicate that central MCH is capable of inhibiting pulsatile LH secretion. We have previously shown that 48‐h fasting suppresses pulsatile LH release in the presence of oestrogen. Take together, these results raise the possibility that MCH could play a role in mediating the suppression of LH secretion during periods of reduced nutrition.