HYPOTHALAMO-PITUITARY-GONADAL AXIS IN CONTROL OF FEMALE REPRODUCTIVE CYCLE ·...

Indian J Physiol Pharmacol 2001; 45 (4) : 395-407

REVIEW ARTICLE

HYPOTHALAMO-PITUITARY-GONADAL AXIS IN CONTROLOF FEMALE REPRODUCTIVE CYCLE

O. P. TANDON* AND RAJESH CHINTALA S.

Department of Physiology,University College of Medical Sciences & GTB Hospital,Shahdara, Delhi - 110 095

(Received on January 18, 2001 )

Abstract : Gonadotropin-releasing hormone (GnRH) secretion from thehypothalamus is pivotal to the regulation of reproductive physiology invertebrates. The characteristic periodic secretion of gonadotropin releasinghormone (GnRH) from the medial basal hypothalamus (MBH), at the rateof one pulse an hour is essential for the maintenance of the menstrualcycle. These pulses are due to oscillations in the electrical activity of theGnRH pulse generator in the MBH. The GnRH pulse generator is underthe influence of an assortment of interactions of multiple neural, hormonaland environmental inputs to the hypothalamus. Hence, a number ofconditions such as stress, drug intake, exercise, sleep affect the activityof this pulse generator. Any deviation of normal frequency results indisruption of normal cycle. The cycle can become anovulatory in thehypothalamic lesions and can be restored by exogenous administration ofpulsatile GnRH.

Of late, studies have shown that pulse generator activity is alsomaintained by specific metabolic signals meant for energy homeostasis.Studies are in progress to work out cellular basis of GnRH pulse generator'srhythmic activation and role of Ca+ as second messenger for GnRHstimulated gonadotropin release. New concepts are emerging to find theexistence of an FSH releasing factor, which independently regulates theactivity of FSH.

Key words : GnRH pulse generator gonadotropins neuro-endocrine

INTRODUCTION the required effect on the gonads. These areinfluenced by diverse, possibly opposing,external and internal environmental signalswhich are recognized, interpreted, collatedand transduced into a specific neuro-humoral direction, which guide the brainand pituitary, to meet the body's changingphysiological needs (1, 2, 4, 5, 6, 7). Neural

The regulation of the reproductive cyclein humans is under the influence of a rangeof neuro-endocrine processes (1,2,3). Themain components of this system are thepituitary, the hypothalamus, which incognizance with higher centers, brings about

396 Tandon and Chintala

inputs from -the limbic area, to the medialbasal hypothalamus (MBH), have beenquantified during estrous cycle (8) andfurther their interactions with the immunesystem has also been worked out (8).Over the past 4 decades, a number ofconcepts have evolved and that often havebeen modified, which has explained andstrengthened the understanding of thiscomplex interaction. Our data have shownthat neural substrate in MBH regulates notonly endocrine events, but also thoseinvolved in immune responses during anovulatory estrous cycle (8, 12, 15). This isimportant for the clinical relevance,such as linking various psychologicalfactors to structural, immunological orpathological abnormalities to the disruptionof the axis. As a result GnRH analoguesare currently being used for thetreatment of prostate cancer, endometriosis,precocious puberty and induction ofovulation (20).

This article provides with a briefoverview of the current concepts of neuro-endocrine involvement in the control ofgonadotropin secretion as studied inrecent years. This will be useful in theunderstanding of the complex hithertomysterious mechanisms, such as stress, diet,exercise, and other diverse influences on thepituitary gonadal axis. We have mainlyconcentrated in discussing the structuresinvolved in the control of the hypothalamo-pituitary axis.

Role of hypothalamo-pituatry axis in control offemale ovarian cycle

The two major sites of action within thebrain, which are important in the regulation

Indian J Physiol Pharmacol 2001; 45(4)

of reproductive function, are thehypothalamus and the pituitary gland. Overthe years the concept of pituitary as themaster gland has given way to a new notionof the hypothalamus as the conductor, whichresponds to both peripheral and centralnervous system messages and exerts itsinfluence by means of neurotransmitterstransported to the pituitary via the portalvessels (1, 2, 7, 9, 10). Whatever theregulating influence from the highercenters, the menstrual cycle is broughtabout by the sex steroids produced withinthe ovarian follicle. This is possible by thefeedback mechanism of the sex steroids onthe gonadotropins on the anterior pituitary(1, 2, 7, 9).

The hypothalamus acts as a centrals t a t'i on where neural and hormonalmessages arising from internal and externalstimuli are decoded and the appropriatemessage sent to the anterior pituitary. Asearly as in 1930, Moore-Pierce theoryattempted to explain the reciprocal influencebetween the gonads and the pituitary (7).The feed back principle was explained asthe see-saw or the push-pull effect. ErnstScharrer in 1928 proposed that the neuronshave a secretory function, where thechemical nature of the neurohormonesvary, ranging from biogenic amines tosmall peptides (1, 2, 7). Until the 1940's,the concept of the anterior pituitary asthe master gland that controls thegonads, adrenal cortex, and thyroidheld good. The role of external factorssuch as the day length on the breedingcycle In rabbits and preovulatoryblockade of LH surge by certain neuralblocking drugs were suggested by Marshallet al (7).


Anatomy of the hypothalamo-hypophysealtract

The hypothalamus is situated at thebase of the third ventricle, in the areabetween the optic chiasma anteriorly,and the mammillary bodies posteriorly.There is however a lack of clearunderstanding in the boundaries betweenthe cellular nuclei of the hypothalamus .(9).Anatomically the functional components aredivided as:

(i) . The hormones of the hypothalamic-neurohypophyseal tract (poster iorpituatry) : These are the directneurosecretory fibers of thehypothalamus, discharging theirsecretions in the systemic blood.Vasopressin and oxytocin aresynthesized in the para-ventricularand the supra-optic nuclei of thehypothalamus and are transportedvia the hypothalamo-hypophysealtract to the posterior pituitary (1,2, 5).

(ii) The hormones for the anteriorpituitary are secreted at themedian eminence. They are thentransported to the anterior pituitaryvia a specialized hypothalamic-pituitary portal system. Most ofthe hormones are hypothalamicreleasing and/or inhibitinghormones (1, 2, 7, 9).

(iii) Numerous efferent and afferentpathways connect the hypothalamus(1, 2).

Hypothalamo-Pituitary-Gonadal Axis in Control of Female 397

Median eminence: acts as a receiving stationthat funnels all the neuronal signals to thepituitary. The releasing hormones of thehypothalamus are deposited at the medianeminence to be picked up by the portalvessels and ultimately transported to theanterior pituitary. On the other hand, theneurons from the pre-optic and supra-chiasmatic nuclei traverse the medianeminence to directly terminate at theposterior pituitary (1, 2).

Embryologic development of the hypothalamusand pituitary

1. The anterior pituitary develops as aoutpouching of the foregut in the 5th

week of the intrauterine life. This iscalled the Rathke's pouch which latermigrates to join the posterior pituitaryat the infundibular process (1, 11, 13).

2. The rostral GnRH-releasing cellsmigrate from the medial olfactoryplacode across the nasal septum and intothe forebrain area (11). They migratealong the nervus terminalis to thehypothalamo-septal-preoptic area. Theyare present as a diffuse population ofcells, which are essentially a loosecontinuum from the telencephalicdiagonal band of Broca and the septalnuclei, through the bed nucleus of striaterminalis, to diencephalic areas(encompassing the medial, lateral andperiventricular preoptic areas, anteriorhypothalamus and retrochiasmatic zone).These neurons ultimately impinge on theMedian Eminence and control theadenohypophyseal secretions (11).

398 Tandon and Chin tala

Gonadotropin Releasing hormone (GnRH):

(luteinizing hormone releasing hormone;LHRH).

Initially it was assumed that thesecretion of each anterior pituitary hormonewas controlled by the action of bothreleasing and inhibiting substancesproduced by the hypothalamus. Hence twohormones were believed to exist as the FSH-releasing hormone and LH-releasinghormone (14, 16). The hormone was laterisolated and characterized as the luteinizinghormone releasing hormone. As thishormone also affected the secretion of FSHit was named as Gonadotropin Hormonereleasing hormone (GnRH) (4, 17, 19).

The porcine GnRH was synthesized andcharacterized by Schally and Guillemin(1971). The gene sequence was isolated onchromosome 8 in 1984 by Seeburg et al(18,19-) Chemically it is a decapeptide,derived from the post-translationalmodification of its pre-pro form. Theneurons in the arcuate nucleus produce thishormone and secrete it in the medianeminence (19). It is then transferred to theanterior pituitary, causing the productionof FSH and LH.

In response to the GnRH stimulation theanterior pituitary produces LH and FSH.The LH production is prompt reaching thepeak in _5 minutes and FSH peak in 30minutes (7, 9). GnRH has a very short half-life (2-4 minutes) making it very difficultto measure its levels in the serum. Thelevels can however be estimated indirectlyby measuring the serum levels of LH (9). Inthe experimental set up the GnRHestimation is possible by the push-pull


cannula method, by sampling thehypophyseal portal blood. Theseexperiments have been carried out on ratsand the rhesus monkeys (22).

GnRH neuronal system

In mammals the GnRH neurosecretorysystem morphologically consists of adiffuse network of about 800-2000functionally connected neurons (13,23). Thecharacterization of these neurons is doneusing the immuno-cyto-chemical technique,by staining the GnRH-immunoreactiveneurons. The GnRH neurons are typicallyoval or fusiform in shape; with simple,unbranched dendritic processes from one orboth poles of the cell (13). Axons emergeeither directly from the cell body or from adendrite. These neurons have a large,centrally placed nucleus and a thincytoplasm. The cytoplasm contains manystacks of rough endoplasmic reticulum,Golgi bodies, and neurosecretory granules.The neurons show a typical pulsatilesecretion, this is typically species specificof a frequency of 20 min to 2 h, which isessential for the expression of the hormone(5, 13, 17, 24).

Physiological features:

a. Pulsatile and intermittent secretion:the mean level of the hormonevaries through the menstrual cycle.A unique feature about the hormoneis a circhoral secretion of one pulseper hour. This pattern of secretionis responsible for the physiologicaleffects of the hormone (26, 28, 29,31, 34).


b. Continuous secretion causesdesensitization and completerefractoriness of the pituitary glandto gonadotropin secretion leading togonadal suppression. (6, 25, 28, 30).

c. If the frequency of the pulses arenot in the physiological range of onepulse per hour, normalgonadotropin hormone secretioncannot occur. Any increase or adecrease will abolish thegonadotropin secretion (27, 28, 32,33).

d. If the frequency of GnRH is re-established in the physiologicalrange of one pulse per hour, normal28-day menstrual cy:~les begin (28,32).

e. Developmental pattern : anotherfeature of this hormone is that itshows a developmental pattern inits secretion. In the infants, thegonadotropin secretion is activeduring the neonatal period, as earlyas the 55 day of the intra-uterinelife. As the foetus matures, theactivity of the GnRH secretingneuron decreases continuously. In

. the .infancy, the secretion is almostquiescent. This continues until theadolescent period. Thereafter areemergence of the GnRH activityis observed, (28, 31) until themenopause wherein the -a ct ivi tycompletely ceases. The fine


tuning of the GnRH neurons occursat the birth, puberty and atmenopause (28).

Hypothalamic-pituitary-ovarian interactions

Menstrual cyclicity and timely ovulationare the result of precise integration of aseries of events occurring wi thin thedifferent components of the reproductivesystem (17, 26). This integrity takes placeat three levels. (i) The activity of the GnRHpulse generator, (ii) The pituitary secretionof gonadotropins and (ii i) The estradiolpositive feedback for the pre-ovulatory LHsurge, oocyte maturation and corpus luteumformation (18).

The GnRH pulse generator : When the GnRHsecreting neurons are deafferentiated, i.e.isolated from all the influences of theanterior pituitary and the higher centers,the neurons have a frequency ofapproximately one discharge per hour (28,29, 34). This cause'S a release of a bolus ofGnRH in to the pituitary portal circulation.The pituitary gonadotropes respond to eachGnRH pulse by discharging a pulse of LHand FSH into the peripheral circulation .During the follicular phase of menstrualcycle the GnRH pulse generator functionsas in the unmodulated state (28, 29) .However, the rise in the levels of estrogenin the follicular phase has a feedbackinhibitory control over the anteriorpituitary. The peripheral levels of estrogencan also alter the activity of the GnRHneurons by a direct or an indirect action(23). Recent evidence suggest the


involvement of neurotransmitters likecatecholamines, gamma-aminobutyric acid,glutamate, neuropeptide Y, neurotensin, ~-endorphin and vasoactive intestinalpolypeptide on the GnRH neurons (23). Itis suggested that estradiol influences theactivity of these neurotransmitters with inthe GnRH network to drive the reproductivecycle (23).

The continued stimulation of theanterior pituitary by the hypothalamus andits inhibition by the feedback mechanismby circulating estrogen creates a balanceand the net effect is an increase in theestrogen levels (1, 12, 28, 29). Hence, inthe follicular phase the estrogen levelscontinuously rise until a threshold level isachieved (-250 pg/ml for >36 hours) (18,28,29). At this level, the inhibitory (negativefeedback) effect of estradiol is suddenlyreversed and the pituitary discharges thepre-ovulatory surge of LH and FSH (positivefeedback) (Fig. 1). The GnRH pulsefrequency or the amplitude is not aprerequisite for this LH surge (28, 29). Theovaries respond to gonadotropin LH surgeby ovulation and a sharp rise in the levelsof estrogen and progesterone (1, 2, 9, 28,29).

i

FoUicular PhaseI

OvuIT LulCal Phase

Fig. 1: Schematic repr ese nt at icn of the pulsatilesecretion of GnRH during the menstrual cycle.


The GnRH pulse generator activity isaffected by the variation in the photoperiodstimulation via the pineal melatonin.Administration of melatonin in the MBHreactivates the GnRH synthesis. (33).Melatonin however also acts directly on thepituitary to produce prolactin. Thus in theanimals it is responsible for the breedingcycles associated with the seasonalvariations (33). The availability of theenergy in the environment also modulatesthe activity of the hypothalamic-pituitary-gonadal axis (31). It function is dependenton the availability of abundant energy inthe environment, any modification in energybalance causing a tilt in the energy balance,suppressing the activity of the GnRH pulsegenerator. Leptins play an important rolein control of this balance (31).

Location of the pulse generator: Autonomoussecretion of GnRH is seen in isolatedhypothalamic nuclei and the activity is mostprominent in the Medic-basal hypothalamus,which corresponds to the Arcuate Nucleus(24). Knobil et al (28, 29) found thatcontinuous stimulation of the medio-basalnucleus caused a decrease In thegonadotropin release. They also recorded theelectrical activity of this area and observeda sudden increase in the multiunit electricalactivity in the medio-basal hypothalamus,which were coincident with the initiationof the LH pulse in the peripheral circulation(30, 34). He further noticed thatprogesterone reduced the frequency of thepulse generator as seen in the luteal phase(28, 29).

Mechanism of action of GnRH : The GnRH hasits receptors on the pituitary gonadotrophs.After binding to the specific receptor, it is


internalized and undergoes degeneration bythe lysosomes. (21, 37, 38, 39). The receptorfragments are rapidly recycled. Anintermittent secretion of GnRH, thusmaintains the activity of the receptor bycontinuous recycling. However oncontinuous exposure to GnRH it producessuppression of LH release, by reducing thenumber of GnRH receptors. (38, 39).

The binding of the GnRH to its receptorcomplex produces a complex series ofintracellular responses, which result insecretion and biosynthesis of the ex and /3subunits of LH and FSH (38, 39). Withinseconds of GnRH binding to the GnRHreceptors (GnRHR) on the pituitarygonadotrophs, intracellular free Ca2+concentration increases (41). This Ca2+ isinitially derived for m the endoplasmicstores, but extracellular Ca2+ enters the cellthrough receptor-regulated voltagedependent Ca 2+ channels. (42) G-proteinsare stimulated which cause the activationof membrane bound phospholipase C, whichinturn activates inosityl triphosphate anddiacyl glycerol. Inosityl triphosphatemobilizes and Ca2+ ions and diacyl glycerolactivates phosphorylating enzyme proteinkinase C (38, 39). Adenyl cyclase is alsostimulated and cAMP is generated. Ca2+ions, protein kinase C and cAMP all theninteract to synthesize and stimulate releaseof stored LH and FSH (2, 38, 39).

Knobil (28) suggested for a normalmenstrual cycle an unvarying hourlypulsatile secretion of GnRH is adequate toobtain the normal 28 day cycle. Thissecretion is in turn controlled by the levelsof estrogen and progestrogen from theovary. However the progestrogen from the


corpus luteum reduces the frequency of thepulse generator, but it does not effect thecylicity of the menstrual cycle as normalcycles can be maintained by a constantstimulation of the GnRH neurons either byelectrical stimulation or by infusion ofhourly GnRH (28, 29).

Other important features noted by Knobilwere (28, 29) :

• GnRH at reduced pulsatilefrequency: One pulse every 3 hoursleads to increase in mean plasmaFSH and decrease in mean LHconcentration in the blood.

• At lower pulses the folliculardevelopment continued albeit witha lower incidence of ovulationcompared with the controls.

• Administration at every 90 minutepermitted initial ovarian cycle, butsubsequent cycles did not culminatein ovulation (29).

• The basalimportant fordevelopment.

LH secretion wasthe normal follicular

• Small changes In the GnRHstimulation have profound effects onthe quality of follicular developmentand any alteration in the frequencyof endogenous GnRH release,occasioned by higher neural centersor other factors, may playa majorrole in the control of ovarianfunction, including the induction ofpuberty (29).


• In ovarectomised monkeys, acharacteristic increase in thecirculating gonadotropins is seen,which reaches steady state inapproximately 3 weeks. This patternis pulsatile and is similar to the onein the non-ovarectomised state albeitlevels are high and is at the rate of1 per hour. This pattern can howeverbe abolished by introduction ofphysiologic concentration ofestrogen. Further the administrationof progestrogen does not cause anyeffect on the gonadotropin secretion.


Hence, estradiol is the principalovarian hormonal component, whichgoverns the tonic gonadotropinsecretion (43,44).

The GnRH Receptor: Hormonal signaling inthe reproductive axis requires intactreceptors for appropriate messagetransduction. GnRH signals through theG protein-coupled receptors (GPCRs).Abnormalities in these receptors, or in theintracellular downstream transductionsystem, results in either enhanced orinhibited gonadal function (38, 45).

mANA4~---(LH betaFSHbetaAlpha Chains)

ATP ~cAMP

/A-klnase

Fig. 2: Mechanism involved in GnRH action on the gonadotrophs.


The GnRH receptor (GnRHR) has aseven transmembrane domain structurewith an exracellular amino terminus anda truncated cytoplasmic tail at itsintracellular carboxyl end. (38) The receptorrequires in tr ace llul ar guanine nucleotidebinding (G) proteins (Gq/G 11) to turn onthe effector enzyme phospholipase C. Thisis turn, enhances inositol triphosphate (IP)production and increases intracellularcalcium, which ultimately leads to thesynthesis and secretion of the gonadotropins(Fig. 2). The human GnRHR gene has threeexons and is located on chromosome 4. Theprincipal location of the receptor is on thecell surface of pituitary gonadotropes (38).These cells, located in the anterior pituitary,respond to GnRH with the synthesis andsecretion of FSH and LH, which mediategonadal steroidoenesis and the developmentof secondary sex characteristics and fertility(38, 40, 45).

The defects in the mutated GnRHreceptor may lead to diminished ligandbinding and/or to altered receptortransduction efficiency. However, no humanmutations lead to constitutive or enhancedGnRHR activity. Agonist stimulationprovokes a conformational change in thereceptor molecule to allow a signaltransduction. This is an efficient processand involves a tertiary complex containingreceptor, G-protein, and effector molecules(Phospholipase C and adenyl cyclase), thatfunction optimally when each proteininteracts with its neighbor at a specific ~ite.These interactions are finally controlled bythe conformation of each componentmolecule. Any variation in the amino acidsequence, by insertion, deletion or change


in the sequence will result in alteredfunction (38, 45).

The other areas where the GnRHR havebeen found are in the hippocampus, inLeydig and granulosa cells, hypothalamusand adenohypophysis- The' current literaturedoes not menion the extra pituitary effectsof the hormone (45).

Interactions with other neurotransmitters

1. Monoamines :

(a) Dopamine : has contradictoryrole. The hypothalamictubheroinfundibular dopaminergicpathway is formed by theseneurons, with cell bodies locatedin the arcuate nucleus. Theaxons project to the medianeminence. When the pituitarycells are coincubated with thehypothalamic fragments and ifdopamine was added the releaseof LH increased, additionof phentolamine a blockerprevented the dopamine inducedLH release. However, in vivo ithas an inhibitory role as seen inhyper prolactenemia where thereis a increase in dopamine whichmay be responsible for thegonadal suppression (1, 23, 44).

(b) Noradrenaline: most experiementalevidence supports a stimulatoryrole of NA in controlling thegonadotropin release. The levelsof ~A are increased prior to the


preovulatory surge of thegonadotropins. Selective blockadeof NA synthesis prevents thepreovulatory LH surge. There isevidence that the NA fiberssynapse with preoptic andanterior hypothalamic nuclei (1,13, 23). However, there seems tobe a differential effect of intra-ventricular LHRH and NE onarcuate nucleus, suggestingultra-short loop negativefeedback affect: (57)

(c) Serotonin: high concentration ofserotonin is found at the medianeminence, with most of theserotonin containing neuron~originating from the raphenucleus In the mid-brain-pons area. Serotonin plays'predominantly a inhibitory role(1, 13, 23).

2. Endogenous opioids : these havepredominantly a inhibitory role in theGnRH secretion. In the in-vitroexperiments, a single dose ofmorphine administered to monkeysbrings about immediate cessation ofthe GnRH pulse generator (43, 46).Administration of the opiodantagonist (Naltrexone) produces anincreased frequency and amplitude ofGnRH and LH secretion. (10, 43).Various stresses in the form ofmechanical physiological orimm unilogical insult result inincrease of corticotropin releasingfactor (CRH), which activates thehypothalamo-pituitary-adrenal axis.CRF can also directly act on GnRH

Indian J Physiol Pharrnacol 2001; 45(4)

neurons causing downGnRH synthesis viarelease. (3, 23, 46)

regulation of~ endorphin

3. Prostaglandin the role ofprostaglandin is not very clear.The brain synthesizes andreleases prostaglandin's. Only theProstaglandin E is important and caninduce the release of GnRH. (1, 23)

The FSH releasing hormone?

Padmanabhan et al (47) have suggestedthe presence of an FSH releasing factor inthe hypothalamus. This is different from theGnRH and causes the release of FSH. Thehormone has not yet been characterized, butan overwhelming evidence for its existenceis present.

The earlier contention that the LH andFSH have a single releasing hormone hasrecently been questioned. A new hypothesishas been put forth by a number of authorsclaiming a separate releasing factor for FSH(47, 48, 49, 50, 51, 52, 53, 54). This has atpresent been labeled as a FSH-releasingfactor as the characterization has not yetbeen carried out and much of the hypothesisis a speculation (47).

Determining the nature of FSH releasingfactor presents as a challenge because it hasa long half-life and has molecularheterogeneity (not all isoforms of FSH havebeen recognized) (47, 48).

FSH release : (Basal and Episodicrelease). In contrast to the absolutedependence of LH secretory system onGnRH pulsatality, the FSH secretion has a


basal (constitutive) and a episodic(regulated) release. Substantial release ofFSH is dependent on the constitutive release(26, 24, 49, 55, 56). A small portion of thissecretion is however episodic and isindependent of GnRH, (48) this accounts forabout 113 of the total FSH thus released.Culler et al (13) have demonstrated that bycombined administration of GnRHantiserum and GnRH antagonist abolishedthe LH pulses without affecting the FSHpulses. All these findings indicate thepresence of FSH releasing factor.

Conclusion

The male and female pattern ofgonadotropin and gonadal secretion isdetermined by different hypothalamicmechanisms. GnRH, secreted by neurons ofthe hypothalamus into the portal system,controls the release of both FSH and LH,which in turn secrete estrogens andprogestrogens. For physiological effects,circhoral GnRH secretion is required. When


the frequency is decreased (x Lzh our ), itresults in suppression of ovulation andprolonged exposure to GnRH also leads toann ovulation by down regulation of thereceptors. Ovarian steroids help inmodulation of GnRH production. Otherfactors are also involved in such regulation.Although the GnRH pulse generator playsan important role in controlling thereproductive cycle and its activity can beidentified electrophysiologically, very littleis known as to (i) what actually establishesthe frequency/amplitude of pulses or inother words, which area in the brain isresponsible for the pacemaker activity of theGnRH cells. (ii) How frequency is modulatedand how is duration of activationdetermined?

Recent evidence has shown that FSH isunder the influence of a separate releasingfactor, it is tentatively known as the FSH,releasing factor. However, its existence isstill speculative as the characterization ofthis molecule has still not been done.

REFERENCES

1. Shaw RW. Control of hypothalamic-pituitaryovarian function; Gynecology 2nd edn, Shaw RW,Soutter PW, Stanton SL (Eds). ChurchhillLivingstone 1997; 171-183.

2. Gordon K, Oehninger S. Reproductive Physiology.Text Book of Gynecology 2nd Edn; Copeland LJ,Jarell JF (Edrs), W B Saunders Company 1993;59-63.

3. Tellam DJ, Yasmin NM, Lovejoy DA. Molecularintegration of hypothalamo-pituitary-adrenal axis-related neurohormones on the GnRH neuron.Biochem. Cell Bioi 2000; 78: 205-216.

4. Chappel SC. Neuroendocrine regulation ofluteinizing hormone and follicle stimulatinghormone: a review. Life Sciences 1985; 36: 97-103.

5. Everett JW. Central Neural Control ofReproductive functions of the Adenohypophysis.Physiol Rev 1964; 44 (3): 373-431.

6. Knobil E. The neuroendocrine control of themenstrual cycle. Recent Prog Horm Res 1980; 36:53-88.

7. Yen SSC. The human menstrual cycle:neuroendocrine regulation: Yen SSC, JaffeRB(eds) : Reproductive Endocrinology 3rd Edn.Philadelphia: WB Saunders Company 1991-. 273

8. Tandon OP, Akema T, Kawakami M. Medial pre-optic unit responses to stimulation of medialamygdala and dorsal hippocampus during differentphases of estrous cycle in the rats. Proc IndianNat Sci Acad 1982; B49: 244-248.


9. Speroff L,. Glass RH, Kase NG.Newuroendocrinology. Clinical GynecologicEndocrinology and Infertility 3rd Edn. Williamsand Wilkins Co. Baltimore,- Maryland, USA 1984;41-75.

10. Wildt L, Leyendecker G. Induction of ovulation bythe chronic administration of naltrexone inhypothalamic amonorrhoea. Clin Endocrinol Metab1987; 64: 1334

11. Schwanzel-Fukuda M, Blick D, Pfaff DW. Originof luteinizing hormone-releasing hormone neurons.Nature 1989; 338:161

12. 'I'andon OP, Electrophysiological correlation ofneuroendocrine and immune responses inproestrous rats. Annals NY Acad Sci 1992, 650:68-73.

13. Bahr MJ. The Neuroendocrine System; Gold JJ,Josimouch JB. Gynecological Endocrinology 4thEdn. Plenum Publishing Corporation, NY. 11-22.'

14. Scally AV, Arimura A, Kastin AJ. Hypothalamicregulatory hormones. Science 1973; 179: 341.

15. Tandon OP, Kawakami M, Akaema T, Ohno S.Medical pre-optic responses to stimulation of limbicand brains tern areas in proestrous rats.Neurosciences 1982, 7 supp 320-327.

16. Scally AV, Arimura A, Kastin AJ. Gonodotropin-releasing hormone: one polypeptide regulatessecretion of luteinizing and follicle stimulatinghormones. Science 1971b; 173: 1036.

17. Crowley WF Jr, Filicori M, Spratt DI, Santoro NF.The physiology of gonadotropin-releasing hormone(GnRH) secretion in men and women. Recent ProgHorm Res 1985; 41: 473-531.

18. Handelsman DJ, Swerdloff RS. Pharmacokineticsof gonadotropin-releasing hormone and its analogs.Endocr Rev 1986; 7: 95-105.

19. Weiss J, Crowley WF Jr, Jameson JL. Normalstructure of the gonadotropin-releasing hormone(GnRH) gene in patients with GnRH deficiency andidiopathic hypogonadotropic hypogonadism. ClinEndocriol Metab 1989; 69: 299-303.

20. Conn MP, Crowley WF. Gonadotropin-ReleasingHormone and its analogues. N Engl J Med 1991;324(2): 93-103.

21. Conn Mp, Staley D, Harris C, Andrews WV, HuckleWR. Mechanism of action of gonadotropin releasinghormone. Ann Rev Physiol 1986; 48: 495-513.

22. Levine JE, Pau KY, Ramirez VD, Jackson 'GL.Simultaneous measurement of leutinizing hormone-


releasing hormone and leutinizing hormone releasein un-anesthetized and ovarectomized sheep.Endocrinol 1982; 111: 1449-55. .

23. Smith MJ, Jennes L. Neural signals that regulateGnRH neurons directly during the estrous cycle.Reproduction 2001; 122(1): 1-10.

24. Sheridan R, Loras B, Rivier J Pasteels JL.Autonomous secretion of follicle stimulatinghormone by long-term organ cultures of ratpituitaries. Endocrinol 1979; 104: 198-204.

25. Belchetz PE, Plant TM, Nakai Y Keogh EJ, KnobilE. Hypophysial responses to continuous andintermittent delivery of hypothalamicgonadotropin-releasing hormone. Science 1978; 202:631-3.

26. Clarke IJ, Cummins JT. The temporal relationbetween gonadotropin releasing hormone (GnRH)and leutinizing hormone (LH) secretionin ovarectomized ewes. Endocrinol 1982; 111:1737-9.

27. Filicori M, Santoro N, Merriam GR, Crowey WFJr. Characterization of the physiological patternof episodic gonadotropin secretion throughput thehuman menstral cycle. J Ciin Endocrinol Metab1986; 62: 1136-1144.

28. Knobil E. Hypothalamic Pulse generator governsmammalian reproduction. News in. Physiol Sci1987; Vol 2: 42-43.

29. Knobil E, Plant TM. Neuroendocrine control ofGonadotropin secretion in the female Rhesusmonkey. Frontiers in Neuroendocrinology, Vol 5,Raven Press, New York 1978.249-264.

30. Phol CR, Richardson DW, Hutchison JS, GermakJA, Knobil E. Hypophysiotropic signal frequencyand the functioning of the pituitary-ovarian systemin the Rhesus Monkey. Endocrinol 1983; 112(6):2076-2080.

31. Lincoln G. Melatonin modulation of prolactinand gonadotrophin secretion. Systems ancientand modern. Adv Exp Med Biol 1999; 460:137-153.

32. Waldhauser F, Weibenbacher G Frish H, PollackA. Pulsatile secretion of gonadotropins in earlyinfancy. Eur J Pediatr 1981; 137: 71-74.

33. Caprio M, Fabbrini E, Isidori AM Aversa A, FabbriA, Leptin in reproduction. Trends EndocrinolMetab 2001; 12(2): 65-72.

34. Wildt L, Hausler A, Marshall G, Hutchison JS,Plant TM, Belchetz PE, Knobil E. Frequency andamplitude of GnRH stimulation and gonadotropin


secretion in the rhesus monkey. Endocrinol 1981;109: 376-385.

35. Wilson RC, Kesner JS, Kaufman JM. Centralelectrophysiological coorelates of pulsatileluteinizing hormone secretion in the rhesusmonkey. Neuroendocrinol 1984; 39: 256.

36. Jakacki RI, Kelch RP, Saunder SE, Loyd JS,Hopwood NJ, Marshall JC. Pulsatile secretion ofLeutinizing hormone in children. J Clin EndocrinolMetab 1982; 55: 453-458.

37. Brown P, McNeilly AS. Transcriptional regulationof pituitary gonadotropin subunit genes. Rev ofReprod 1999; 4: 117-124.

38. Conn PM, Huckle WR, Andrews WV, McArdle CA.The molecular mechanism of action of gonadotropinreleasing hormone (GnRH) in the pituitary. RecentProg Horm Res 1987; 43: 29-68.

39. Huckle W, Conn PM. Molecular mechanism ofgonadotropin releasing hormone action. II. Theedffector system. Endocr Rev 1988; 9: 387-95.

40. Marshall JC, Dalkin AC, Haisenleder DJ, GriffinML, Kelch RP. GnRH pulses-the regulators ofhuman reproduction. Transactions of the AmericanClinical and Climatological Association 1992; 104:31-46.

41. Marian J, Conn PM. Gonadotropin releasinghormone stimulation of cultured pituitarycells requires calcium. Mol Pharmacol 1979; 16:196-201.

42. Hansen JR, McArdle CA, Conn PM. Relative rolesof calcium derived form intra- and extracellularsources in dynamic leuitinizing hormonerelease from pituitary cells. Mol Endocrinol 1987;1: 808-815.

43. Besch NF, Smith CG, Besch PK, Kaufman RH. Theeffect of marihuana (delta-9-tetrahydrocanabinoDon the secretion of lutinizing hormone in theovarectomized rhesus monkey. Am J ObstetGynecol 1977; 128: 635.

44. Richardson DW, Goldsmith LT, ·Pohl CR,Schallenberger E, Knobi! E. The Role of Prolactinin the regulation of the Primate Corpus Luteum.J Clin Endocrinol Metab 1985; 60(3): 501-504.

45. Cohen DP. Molecular Evaluation of theGonadotropin-Releasing hormone receptor.Seminars in Reprod Med 2000; 18(1):11-16.

46. Smith CG, Besch NF, Smith RG, Besch PK. Effectof tetrahydrocannabinol on the hypothalamic


pituitary axis in the ovarectomized Rhesus monkey.Fertil and Sterilit 1979; 31: 335-339.

47. Padmanabhan V, McNeilly AS. Is there an FSH-releasing factor? Reproduction 2001; 121: 21-30.

48. Padmanabhan V, McFadden K, Mauger DT, KarschFJ, Midgely AR. Neuroendocrine control of FSHsecretion 1. Direct evidence for separate episodicand basal components of FSH secretion. Endocrinol1997; 138: 424-432.

49. DePaolo LV, Bisak TA, Erickson GF, Shimasaki S,Ling N. FoHistatin and activin: a potential intrinsicregulatory system within diverse tissues. Proc ofthe Society for experimen.tal Biology and Med 1991;198: 500-512.

50. Savoy-Moore RT, Schwartz NB. Differential controlof FSH and LH secretion. International Review ofPhysiol 1980; 3: 65-68.

51 Thomas SG, Clarke IJ. The positive feedback actionof estrogen mobilizes LH-containing but not FSH-containing secretory granules in ovinegonadotoropes. Endocrinol 1997; 138: 1347-1350.

52. McNeilly AS. The control of FSH secretion. ActaEndocrinologica Supple 1988; 122: 287-292.

53. Lescheid DW, Terasawa E, Abler LA, Urbanski HF,Warby CM, Millar RP, Sherwood NM. A secondform of gonadotropin-releasing hormone (GnRH)with characteristics of chicken GnRH-II is presentin the primate brain. Endocrinol 1997; 138: 5618-5629.

54. Dhariwal APS, Nal lar R, Batt M, McCann SM.Seperation of follicle-stimulating hormone-releasing factor from luteinzing hormone-releasingfactor. Endocrinol 1965; 76: 290-294.

55. Culler MD, Negro-Vellaar A. Pulsatile folliclestimulating hormone secretion is independent ofluteinizing hormone releasing hormone (LHRH):pulsatile replacement of LHRH bioactivity inLHRH- immunoneutralized rats. Endocrinol 1987;120: 2011-2021.

56. McCann SM, Mizunuma H, Samson WK, LumpkinMD. Differential hypothalamic control of FSHsecretion: a review. Psychoneuroen docrinol 1983;8: 299-308.

57. Krieg RJ, Tandon OP, Whitmoyer DI, Sawyer CH.Differential effects of intraventricular Luteinizinghormone releasing hormone (LH-RH) andNorepinephrine on electrical activity of the arcuatenucleus in the proestrous rat. Neuroendocrin.ology1976; 22: 152-163.

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HYPOTHALAMO-PITUITARY-GONADAL AXIS IN CONTROL OF FEMALE REPRODUCTIVE CYCLE ·...

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