aromatase 4

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Endocrine and metabolic changes in women with polycysticovaries and with polycystic ovary syndrome

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2.4. Biochemical and clinical features of PCOS

2.4.1. Gonadotrophins in PCOS

2.4.1.1. Inappropriate gonadotrophin secretion

An inappropriate gonadotrophin secretion is associated with the classic form ofPCOS. Compared with the follicular phase of the normal menstrual cycle womenwith PCOS exhi!it a disproportionately high "# secretion with relatively constantlow $S# secretion %&acArthur et al.'()* +en et al.'(,-. /herefore an

elevated "#0$S#1ratio of 213' is commonly used to indicate a!normalgonadotrophin secretion. /he prevalence of increased serum "# in PCOSranges from -4 to (- 4 %Conway et al.'(*( $ran5s '(*(. /he reasons forthese varied estimates pro!a!ly include the heterogeneity of PCOS different!lood sampling fre6uencies and the specificity of the gonadotrophin assays used.7t has !een shown that the mean of two "# values in samples collected at -1min interval significantly reduces random sample varia!ility %Apter et al.'((8!.

An increased "#1pulse fre6uency in PCOS women independent of !ody massindex %9&7 or adiposity is well esta!lished %:aldstreicher et al.'(** &oraleset al.'((;. 7t has !een suggested that gonadotrophin defects particularly an

excess of serum "# is a predominant finding in hyperandrogenic womenwhether they !e adolescents or older perimenopausal women %Apter et al.'((8a /aylor 2---!. /he underlying cause of this pattern of gonadotrophinsecretion is lin5ed to an accelerated gonadotrophin releasing hormone %


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2.4.2.1. Androgen secretion

Androgens and androgen precursors are secreted !y !oth the ovaries andadrenal glands in response to their respective trophic hormones "# andadrenocorticotropic hormone %AC/#. /he initial and the rate1determining step

in the !iosynthesis of all steroid hormones is the conversion of cholesterol topregnelone carried out !y the cholesterol side chain cleavage en=yme %P8)-scc%$igs and 8 %Rosenfield '(((. P8)-c', possessing !oth ',@1hydroxylaseand ',2-1lyase activities is the rate1limiting step in the formation of steroidhormones in the adrenals and in the gonads. 9oth en=ymatic activities of theprotein are encoded !y a single gene C+P',. /he expression of this gene isa!solutely dependent on the concentration of trophic hormones "# in ovary%&agoffin '(*( and AC/# in the adrenal cortex %Fohn et al.'(*;. /wo en=ymesthat are not mem!ers of the P8)- gene family are also important for adrenal andgonadal steroid synthesis3 @1hydroxysteroid dehyrogenase type 77 % 1#SG 77which is exclusively expressed in adrenal gland and gonads %Rheaume et al.

'((' and steroid acute regulatory protein a transporter of cholesterol from theouter to inner mitochondrial mem!rane %"in et al.'(().

2.4.2.2. Ovarian steroidogenesis

Normal ovarian function depends on the com!ined action of "# on the theca1interstitial1stromal cells and $S# on granulosa cells %$ig . According to the two1cell model of ovarian function steroidogenesis is organi=ed there!y that thetheca cell compartment secretes A in response to "# and A is then convertedwithin granulosa cells to estrogen !y aromatase under the influence of $S#. As

dominant follicle emerges !oth increased amounts of A and ?2are secreted !ut?2comes to predominate. Androgen synthesis must !e 5ept to the minimumnecessary to optimi=e follicular development. Although androgens are o!ligatesu!strates for ?2synthesis an excess of androgens seem to interfere with theprocess of follicular maturation preventing the selection of the dominant follicleand committing the follicle to atresia %#illier > /etsu5a '((, as well as interferingwith the "# action on luteini=ed granulosa cells %Polan et al.'(*;.

Several studies have indicated that polycystic ovaries usually produce excessandrogen %Hirschner et al.'(,; Chang et al.'(* Rosenfield '(((. Chronic"# stimulation in PCOS induces sustained hypersecretion of androgens !y thetheca compartment %+en et al.'(,-. /heca cells are shown to secrete a!normalamounts of steroids in culture !oth !efore and after "# stimulation %


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igure 4. ;a0or steroid pathways in the adrenal corte. /he s8uare containsthe core steroidogenic pathways also used by the gonads. 9n the adrenals&*%hydroyprogesterone )*%O#P- is situated at a potential branch point atwhich cortisol and se hormone synthesis may diverge depending onwhether *%O#P undergoes 2*%hydroylation )pathway to cortisol- or *&26%lysis )pathway to *%3etosteroids-. Cytochrome 476 en1yme steps are sidechain cleavage> *'%hydroylase(*&26%lyase> 2*%hydroylase )2*-> **$%hydroylase(*@%hydroylase%dehydrogenase )**& *@-. Aon%P476 en1ymesteps are steroidogenic acute regulatory protein )St! ?7%isomerase%$%hydroysteroid dehydrogenase )$ -& *$ %hydroysteroid dehydrogenase)*$ -& sulfo3inase )S- and sulfolyase )S"-. 5ashed pathways areconsidered to be relatively minor. Conversion of dehydroepiandrosterone)5#E!- to 5#E! sulphate and androstenedione to **$%hydroyandrostenedione ta3es place in the 1ona reticularis.5eoycorticosterone )5OC-. );odified from


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2.4..4. &olecular mechanisms of insulin resistancein !CO'

7nsulin action is initiated when insulin !inds to its cell surface receptor %$ig ).

/he insulin receptor !elongs to a family of protein tyrosine 5inase receptorswhich includes the 7


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membrane& and glucose upta3e is stimulated. /he 9 scc = side chain cleavage> c= cytochrome> arom = aromatase>%S%S%= disulphide bonds> :lucose%,%P = :lucose , phosphate

"igand !inding induces autophosphorylation of the insulin receptor on specifictyrosine residues and increases the intrinsic tyrosine 5inase activity of the 1su!unit. /he activated insulin receptor then tyrosine phosphorylates intracellularsu!strates to initiate signal transduction. Over the last few years several of thesesu!strates have !een characteri=ed such as insulin receptor su!strates ' and 2

%7RS1' and 2 which !ind to signaling molecules such as the specific domain ofthe phosphatidylinositol 15inase %P7 5inase a necessary step in theinitiali=ation of glucose transport %Saltiel '((;a :hite '((*. 7RS1' is re6uiredfor insulin1mediated translocation of the intracellular pool of glucose transporters%


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7ncreased insulin1independent serine phosphorylation in PCOS fi!ro!lasts seemsto !e a uni6ue disorder of insulin action as other insulin1resistant states such aso!esity type 2 G& type A syndrome and leprechaunism do not exhi!it thisa!normality %Gunaif et al.'(()!. A significant decrease in muscle 7RS1'1associated P715inase activation during insulin infusion has !een reported in

PCOS women consistent with a defect in the early steps of insulin receptorsignaling %Gunaif '(((. $ollicles in polycystic ovaries were recently shown tohave decreased staining for 7RS1' in granulosa cells and increased staining for7RS12 in theca cells compared with follicles from ovulatory ovaries %:u et al.2---.

Protein 5inase A could !e the factor which induces serine phosphorylation in theinsulin receptor there!y causing insulin resistance and also serine1phosphorylates P8)-c',@ causing hyperandrogenism. /his could explain theassociation of PCOS and insulin resistance %hang et al.'(() Gunaif '((,. 7thas !een suggested that the factor responsi!le for the increased serine

phosphorylation could !e genetically programmed %Gunaif '(((. /hese findingsare in accordance with recent twin and family studies where insulin resistanceappeared to !e a genetic defect in PCOS %"egro '((*a.

2.4..(. Insulin action in polycystic ovary

/he possi!le mechanisms causing post!inding defects in insulin action in womenwith PCOS are shown in $ig. ;. 7nsulin alone can act as a gonadotrophin in thenormal ovary !ut under physiologic conditions is li5ely to interact withgonadotrophins as well as with paracrine ovarian factors such as 7


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has !een concluded that insulin action to the ovary is mediated !y way of its ownreceptor rather than !y cross1reaction with 7 $ran5s '(() Nestler et al.'((*a. 7t is possi!le that insulin action in the cells from PCOS ovaries mayinvolve inositolglycans in postreceptor signaling and this pathway could provide

an alternate means of signal transduction in otherwise insulin1resistant tissues%Nestler et al.'((*a Porets5y et al.'(((.

igure ,. 9nsulin action in women with PCOS. Possible mechanismscausing postbinding defects in insulin action in women with PCOS.5ecreased insulin%dependent receptor tyrosine phosphorylation )/yr%P- andincreased constitutive receptor serine phosphorylation )Ser%P-& probablysecondary to a cell membrane associated factor& inhibits insulin receptorsignaling. 9nhibition of receptor signaling leads to decreased amount ofglucose transporters and decreased glucose upta3e. Ser%P of insulinreceptor substrate%* )9


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adrenal venous effluents levels of 7


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2.4.". #eptin and PCOS

"eptin a ';, amino1acid protein transcri!ed from the o"gene was discovered!y hang et al. '((8. 7n o!ese hyperphagic homo=ygote o"-o" mice twomutations of the o" gene was demonstrated to lead to a lac5 of leptin %hang et

al.'((8. "eptin is produced mainly in fat cells. /he secretion of leptin hasultradian and circadian fluctuations %Sinha et al.'((; "icinio et al.'((, and isenhanced !y glucocorticoids and insulin %9oden et al.'((, Papaspyrou1Rao etal.'((,. "eptin plays an important role in the regulation of !ody1fat mass inanimals and in humans %#alaas et al.'((). Secreted leptin appears to !ind toone or more proteins in the circulation %Sinha et al.'((;. "eptin achieves mostof its meta!olic effects !y interacting with specific receptors located in the centralnervous system and in peripheral tissues %/artaglia et al.'(() "ee et al.'((;./he leptin receptor is a class 7 cyto5ine receptor %7hle '((;. Several lines ofevidence suggest that the hypothalamus is a critical target for the satiety effectsof leptin %#alaas et al.'(() ?ric5son et al.'((;. /he complete set of genes

involved in mediating the downstream effects of activation of the central leptinreceptor and of transcription factors on energy meta!olism is un5nown. Onecandidate effector molecule is the hypothalamic neuropeptide + %NP+ a potentstimulator of food inta5e of which synthesis is inhi!ited !y leptin %Stephens et al.'(() ?ric5son et al.'((;.

7nsulin resistance is associated with elevated plasma leptin concentrations%Segal et al.'((; Dauh5onen et al.'((*! and hyperleptinemia has !eensuggested to !e part of the insulin resistance syndrome %de Courten et al.'((,"aivuori et al.2---. Su!cutaneous fat tissue has !een shown to !e a moreimportant determinant of serum leptin levels than intra1a!dominal fat tissue

%Dauh5onen et al.'((*!. /he high levels of leptin in o!esity may reflectresistance of these su!ects to leptin action %9ray > +or5 '((,. #epatic effectsof leptin has !een suggested to contri!ute to insulin resistance %Cohen et al.'((;. "eptin could contri!ute to a hypersecretion of insulin !y the pancreatic 1cell islets in o!ese insulin resistant su!ects %"arsson et al.'((; !ut there isevidence that leptin may also have favoura!le effects on insulin sensitivity%Shima!u5uro et al.'((,.

"eptin administration to the leptin deficient o"-o"mice produces weight loss aswell as restoring ovulation and fertility %#alaas et al.'(() Cheha! et al.'((;. Alin5 !etween serum leptin and "# concentrations during the menstrual cycle has

!een reported in humans %&essinis et al.'((* /eirmaa et al.'((*. A directeffect of leptin on ovarian steroidogenesis is possi!le !ecause messenger RNAfor leptin receptors has !een found in !oth the theca1 and granulosa cells of theovaries %Harlsson et al.'((, and leptin synthesis has also !een demonstratedin ovarian granulosa cells %Cioffi et al.'((,. 7t has !een reported that leptin invitroinhi!its the synergistic action of 7


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/he first report concerning leptin and PCOS suggested that a su!stantialproportion of women with PCOS have leptin levels higher than expected for their9&7 %9r=echffa et al.'((;. "ater studies did not find significant differences inleptin levels !etween PCOS women and weight1 %&ant=oros et al.'((, or fat1mass matched controls %"aughlin et al.'((,. #owever a recent study has

shown that although circulating leptin levels in PCOS women did not differ fromthose in age1 and weight1matched controls the plasma NP+ concentrations weresignificantly higher in non1o!ese and o!ese PCOS women than in controlwomen. /he NP+ concentration in PCOS women remained unchanged in spiteof an increased 9&7. /his may indicate a distur!ed feed!ac5 system in theinteraction !etween NP+ and leptin in o!ese women with PCOS %9aranows5a etal.'(((. 7n a cohort of women with PCOS serum leptin concentrations werefound to !e 2-4 lower than in controls with similar 9&7 across a wide range of!ody weights. 7t is therefore possi!le that insulin1stimulated leptin secretion islimited !y insulin resistance in adipocytes in PCOS women %Faco!s > Conway'(((. $urthermore visceral fat has !een shown to secrete less leptin than

su!cutaneous fat %Dauh5onen et al.'((*! Dan #armelen et al.'((* whichmay lead to decreased satiety signals in the hypothalamus permitting furtherdevelopment of o!esity %Faco!s > Conway '(((.

A new signaling molecule resistin has recently !een discovered which isinduced during adipogenesis and secreted !y adipocytes. Resistin levels areincreased in diet1induced o!esity as well as in genetic models of o!esity andinsulin resistance. 7n adipocytes neutrali=ation with resistin antiserum enhancedinsulin1stimulated glucose upta5e and insulin action was !lunted !y recom!inantresistin. /he administration of resistin to mice impaired glucose tolerance %7


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A genetic !asis for the Stein1"eventhal syndrome was suggested !y Cooper andcolleagues in '(;* %Cooper et al.'(;*. /hey studied '* families in which thesyndrome appeared in a pattern consistent with a dominant mode of inheritance.&any later studies have also suggested a dominant mode of inheritance%$erriman > Purdie '(,( #ague et al.'(** "unde et al.'(*( Carey et al.

'((


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igure @. Aatural history of women with PCOS.

Prev #ome NextClinical features ofPCOS

p "ong1term se6uelaeand ris5s in PCOS

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