Recent Advances in Gyne-Endocrinology Dilip Kumar Dutta
INDEX
×
Chapter Notes

Save Clear

Neuroendocrine Control of Reproduction1

Subash Chandra Biswas
 
INTRODUCTION
“Beauty is brain deep” so is the sexuality. “Reproduction is also brain deep”. Brain is the major site of regulation of reproductive function. It is the synchronized action of hypothalamopituitary-ovarian axis which makes the reproductive orchestra to play at a perfect tune. Previously it was thought that pituitary is the band master of this orchestra but now recent advances say that hypothalamus is the band master of the orchestra. But within the last decade a new emerging concept is appearing which dictates that it is the denovo follicular microenvironment which gets its role programmedin utero actually masterminds the total synchrony.1
 
THE NEUROHORMONE CONCEPT AND HYPOTHALAMO HYPOPHYSEAL PORTAL SYSTEM
The total neuroendocrine control system runs through a special portal circulatory system, which is needed to understand before exploring the whole control mechanism. Superior hypophyseal arteries, which form a dense network of capillaries in median eminence of hypothalamus, drain into portal vessels that descend down to anterior pituitary through pituitary stalk. Some neuroendocrine/neurohormonal agents, mainly peptide in nature, originate in hypothalamus and releases into this portal circulation. They have positive or negative influence on secretion of tropic hormones from pituitary. This classic neurotransmitter or neurohormones take the main lead in control system.
These neurohormones are named as releasing or inhibitory hormones according to their positive or negative regulatory action on pituitary tropic hormone respectively. The main releasing neurohormone controlling reproductive system is gonadotropin releasing hormone (GnRH) and the inhibitory one is dopamine. Apart from GnRH, corticotropin-releasing hormone (CRH) can also suppress gonadotropin secretion partly via endorphin (Fig. 1.1).2
zoom view
Fig. 1.1: Pituitary and hypothalamus hormone control
 
The HPO Axis (Hypothalamopituitary-Ovarian Axis)
There are releasing hormones, tropic hormones and target hormones which in turn control the central hormones through feedback mechanism. For reproductive system, the releasing hormone is GnRH, tropic hormones are FSH and LH and main target hormones are estrogen and progesterones. Gonadotropin-releasing hormone (GnRH) reach the anterior pituitary in high concentration and binds to the GnRH receptors on the gonadotropic cells of anterior pituitary to stimulate the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to the circulation. The pulsatile secretion pattern of GnRH induces the cyclic release of LH and to a lesser extent of FSH. The FSH act at target organ ovary and induces follicle growth and subsequently estradiol and inhibin secretion by the granulosa cells. Estradiol at a minimal concentration exerts a negative feedback effect on pituitary as well as on hypothalamus and decrease further secretion of GnRH and tropic hormones. But high levels of estradiol, produced by mature follicles, lead to a positive feedback on the hypothalamus at time of proestrus, which causes the LH surge responsible for ovulation (Fig. 1.2).
We will further restrict our discussion organ wise rather than individual hormone wise. So, our organs are hypothalamus-pituitary-ovary/ reproductive end point.
During this period, inhibin is secreted by the granulosa cells which cause inhibition of FSH release.
After ovulation, the luteinized granulosa and the theca cells start to produce high levels of progesterone, which in turn inhibits LH and FSH secretion from the pituitary. Thus, the whole control loop completes its action on regulating reproductive system.
3
zoom view
Fig. 1.2: Pituitary ovarian cycle
 
HYPOTHALAMUS AND NEUROHORMONES
Hypothalamus is the major hormone-controlling organ in brain. It is a part of diencephalon at the base of brain that forms the floor of third ventricle. In fact hypothalamus is the conglomeration of different peptidergic neural cells that produce and secrete releasing and inhibitory hormones through axons of neural cells to the hypophyseal portal circulation to reach anterior pituitary. These cells of hypothalamus, which produce, store and secrete neurohormones, share the characteristics of both neurons and endocrine gland cells. They respond to signals in the bloodstream as well as to neurotransmitter. Hypothalamus has two major neurohormones namely GnRH (the realizing hormone) and Dopamine (the inhibitory hormone) particularly responsible for reproductive regulation.
 
GnRH and its Role
GnRH is a decapeptide (Fig. 1.3) produced in the neuronal cells of arcuate nucleus of hypothalamus from a large precursor polypeptide which is controlled by a gene located on short arm of chromosome 8.24
zoom view
Fig. 1.3: Structure of GnRH with 10 amino acids
The cells which produce GnRH originate from olfactory area of developing diencephalon. Cells migrate to their primary location at hypothalamus along cranial nerves connecting nose and forebrain.3 This explains the pathogenesis of Kallmann's syndrome, an association between anosmia and absence of GnRH (a failure of both olfactory axonal and GnRH neuronal migration from olfactory placode) as a form of hypothalamic hypogonadism.4 After migration the GnRH cell bodies are located in arcuate nucleus and GnRH is secreted in portal circulation via axons through the tuberoinfundibular tract.5
 
Secretion
GnRH has a very short half-life. It is between 2 and 4 minutes. It is rapidly degraded and diluted in pituitary portal circulation. Thus, it needs to have a constant release to control the reproductive system function. Arcuate nucleus secretes GnRH in pulsatile fashion within a critical range of frequency and amplitude.6 The frequency being 1 pulse/hour with portal blood level 2 ng/ml.
 
Control
GnRH secretion is controlled by a long feedback loop where the estrogen and progesterone inhibit further GnRH secretion. The short feedback loop exists where the FSH and LH from pituitary exert suppressing action on GnRH. An ultrashort feedback loop also exist where itself GnRH inhibit own release along with some other neurotransmitter like dopamine, norepinephrine, serotonin, endorphin and melatonin. Dopamine and serotonin inhibits release of GnRH7 and gonadotropins as well. Norepinephrine and neuropetide Y stimulate GnRH.8,9 Thus, neuropeptide 5Y is viewed as a valid link between nutrition and reproductive function.10 (Fig. 1.4).
 
Role
The pulsatile secretion of GnRH triggers pulsatile secretion of gonadotropins from pituitary but augmentation of pulsatile pattern of gonadotropin occurs just before puberty with night time increment of LH. In puberty, arcuate activity begins with low frequency and gradually proceeds to a cycle of acceleration of frequency and ultimately reaches to a full adult pattern.11 Ovarian steroids are also released in pulsatile fashion coordinated with LH pulse, the major stimulator of ovarian steroidogenesis. GnRH secretion is more frequent but lower in amplitude during follicular phase compared to luteal phase. This slowing of GnRH pulse frequency in the late luteal phase is essential for rise of FSH for subsequent cycle.12
 
Dopamine
Dopamine is a catecholamine neurotransmitter released by the hypothalamus and act via D2 receptor on pituitary gland. It inhibits the release of prolactin from the anterior lobe of the pituitary. Stimulatory effect of prolactin secretion occurs via TRH, VIP and perhaps GnRH. Dopaminergic mechanism is highly influenced by estrogen. Dopamine secretion is inhibited by estrogen and endogenous opioids. Serotonin, neuropeptide Y and prolactin stimulate dopamine secretion.13
zoom view
Fig. 1.4: Hypothalamus control by Brain
6
 
PITUITARY AND GONADOTROPINS
Anterior pituitary secretes two major gonadotropins FSH and LH. Both LH and FSH are secreted from the same gonadotropes localized at lateral wall of pituitary in response to pulsatile secretion of GnRH. Gonadotropins are also regulated by some intrapituitary autocrine and paracrine actions.14 FSH secretion is increased during follicular phase of menstrual cycle (by direct effect of GnRH). FSH acts on granulosa cells of ovaries by FSH receptor and stimulate aromatization of androgen to estrogen production. Along with it produces activin and inhibin. FSH also increases expression of LH receptors on granulosa as well as theca cells. With adequate estrogen production, estradiol reaches the peripheral threshold level to evoke LH surge through positive feedback at anterior pituitary. LH initiates luteinization and progesterone production from granulosa cells. Rise of progesterone may also facilitate positive feedback action of estrogen. The LH surge initiates meiosis inside oocyte, luteinization and progesterone and prostaglandin production which in turn helps to rupture the follicle wall to initiate ovulation. The elevated progesterone, estradiol and inhibin-A act centrally to suppress gonadotropin and new follicular growth during luteal phase. In case of pregnancy hCG rescues corpus luteum and maintain luteal function till placental steroidogenesis. In case of nonpregnant cycle, regression of corpus luteum involves luteolysis followed by lowering of estrogen production which initiates further increment of FSH for subsequent cycle.
 
OVARY AND HORMONAL CONTROL
Apart from gonadal steroids three important peptides activin, inhibin and follistatin take major part in neuroendocrine control. Activin and inhibins are secreted from ovarian granulosa cells. Activin stimulate and inhibin inhibits FSH secretion. Inhibin may even enhance LH activity.15 Activin augments secretion of FSH by increasing pituitary response to GnRH via enhancing GnRH receptor formation.16 The effect of activin is blocked by inhibin and follistatin.17 Follistatin is basically secreted from gonadotropes of pituitary and inhibit FSH secretion most probably by inhibiting activity of activin.18 On the contrary activin stimulates follistatin production and inhibin prevents this response.19
 
ROLE OF OPIOIDS AND PINEAL GLAND
Endogenous opiates inhibit gonadotropin secretion by suppressing hypothalamic release of GnRH. Both estrogen and progesterone increases action of opiates.20 Melatonin secreted from pineal gland suppresses GnRH secretion which may explain association of blindness with onset of puberty.7
 
SUMMARY: KEY POINTS
  1. Pulsatile GnRH secretion must be within a critical range of frequency and amplitude to maintain normal reproductive function.
  2. GnRH has only positive action on the pituitary: Synthesis, storage, activation and secretion of gonadotropins.
  3. Lower GnRH pulse frequency favors FSH and higher GnRH pulse frequency favors LH secretion.
  4. Lower level of estrogen inhibit FSH secretion, higher level induces LH surge at midcycle.
  5. Higher level of progesterone inhibit pituitary secretion of gonadotropins by inhibiting GnRH pulses at the level of hypothalamus.
REFERENCES
  1. Fukuda M, Fukudu K, Yding Anderson, et al. Characteristics of human ovulation in natural cycle with age and hormonal control. Hum Reprod 2001; 16: 2501.
  1. Heyflick JS, Adelman JP, Seeberg PH. The complete nucleotide sequence of the humal gonadotropin releasing hormone gene. Nucleic Acid Res 1989; 17: 6403.
  1. Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone realizing hormone neurone. Nature 1989; 338: 161.
  1. Waldstrcheir J, Seminara SB, Jameson JL, Gayer A, et al. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human, J Clin Endocrinol Metab 1996; 81: 4388.
  1. Goldsmith PC, Thind KK. Location of neuroendocrine GnRH neurons in the monkey hypothalamus by retrograde tracking and immunostaining. J Neuroendocrinol 1990; 2: 157.
  1. Knobil E. The neuroendocrine control of the menstrual cycle. Rec Prog Horm Res 1980; 36: 53.
  1. Anderson AN, Hagen C, Lange P, et al. Dopaminergic regulation of gonadotrophin levels and pulsatility in nprmal women. Fertil Stril 1987;47: 391.
  1. Herbison AE. Noradrenergic regulation of cyclic GnRH secretion. Rev Reprod 1997; 2: 1.
  1. Pau KF, Berria M, Hess DL, Spice HG. Hypothalamic site-dependant effect of neuropeptide Y on GnRH in rhesus marcaques. J Neuroendocrinol 1995; 7: 63.
  1. McShane TM, May T, Miner JL. Central action of neuropeptide Y may provide a neuromodulatory link between nutrition and reproduction. Biol Reprod 1992; 46: 151.
  1. Backstorm CT, McNelly Al, et al. Pulsatile secretion of LH, FSH, prolactin estrogen and progesterone in normal menstrual cycle. Clin Endocrilnol Etab 1982;16:29.
  1. McCartney CR, Gingrich MB, et al. Hypothalamic regulation of cyclic ovulation: Evidence of gradual restraining effect of progesterone. J Clin Endocrinol Metab 2002;87:2194.
  1. Ben-Jonathan N. Dopamine as a prolactin inhibitor. Endocr Rev 2001; 22: 724.
  1. Ray D, Melmed S. Pituitary cytokine and growth factors and actions. Endocrine Rev 1997;18:206.
  1. 8 Bauer-Dantoin AC, Wess J, et al. Roles of estrogen, progesterone and GnRH in the control of GnRH receptor gene expression at the time of preovulatory gonadotropic surge. Endocrinology 1995; 136: 1014.
  1. Bilezikjian LM, Corrigan AZ, et al. Pituitary follistatin and inhibin subunit messenger RNA level are regulated by local and hormonal effect. Endocrinology 1992; 137: 4277.
  1. Kogwa K, Nakamura T, et al. Activin-binding protein is present in pituitary. Endocrinology 1991; 128: 1434.
  1. Besecke LM, Guendner MJ, et al. Pituitary follistatin regulates activin mediated production of FSH during rat estrous cycle. Endocrinology 1997; 138: 2841.
  1. Besecke LM, Guendner MJ, Bauer-Dantoin AC, et al. GnRH regulates FSH beta gene expression through an activin-follistatin autocrine paracrine loop. Endocrinology 1996; 137: 3667.
  1. Casper RF, Alapin-Rubilovitz S. Progestin increases endogenous opioid activity in postmenopausal women. J Clin Endocrinol Metab 1985; 60: 34.