The ups and Key words @ Endocrine syste esogen Menepause eemone replacement ‘therapy 0) rons wnunde igure 1 Glands ofthe ‘endocrine sytem. 30 downs of hormones This article explains, with particular reference to the female reproductive system, what happens to hormone levels as we age, the effect these changes can have on the body, how these changes can lead to an increased risk of developing certain diseases, and how our knowledge is being used to develop new treatments to target diseases associated with the menopause. ne endocrine system is an information Iignal network that uses chemicals — hormones — to communicate I is hey to body Function — regulating mood evelopment, metabolism and. reproductive processes Hormones ate released from endocrine lands located throughout the body (see Figure 1). They enter the blood and are caried to specific target ‘organs cells sues where hey induce response Pruitay eand Hypothalamus Parties Pancras Ovaries females Testes. ith butcan measured in ‘This peo signalling slow to begin lead 10 prolonged responses, oft days, ach hormone has a defined structure that is recognised by specific binding sites — called hormone receptors — on the target cll Binding ‘of a hormone to is receptor triggers a cascade of secondae effects inside the target cell ultimately activating the expression of genes in that ell (see Box 1) Hormone synthesis and release is controlled bby positive and negative feedback mechanisms, ‘which maintain or restore homeostasis. A well ‘own example i the female menstrual ele Th involves sigaalling network comprising the brain And ovaries [se Butociea Sieers Ree, Vol. 2: No.l pp. 23-27) The menstrual cycle ‘The menstrual cycle of a heathy pre-menopausit ‘woman lasts an average of 28 days, resuking in the release of a fertilisation-competent oocyte The eycle can be split ico three distinct phases, characterised by tightly regulated fluctuations in hormone concentations (se Figure on p.32)-The follicular phase spans the fist day of menstruation though to ovulation. I begins with an intense folile simulating hormone (FSH) concentration Thisstimulates around 15-20 follicles to mature and secrete inceasing quantities of cestogen, which in tamn inhibits further FSH secretion by negative feedback, Usually, 2 single follicle emerges and ‘estrogen concentrations peak towards the end of Bilegil Scones Reiit eee omens canbe grouped bral it str, amines ané pete! Protine (ee Table Hotvanes nach grup ten to frcton in 3 ime ashion Petes ae proteins — the gest ass — are vaiblein sie ranging fom tre to SO ano ate in lens Most peptide hamones are sytheszed inte endopasmc ret of ae ontaned within the endocrine organ as lage bilgi active ecusre,trmedpro-harmanes, The are stredinseeory ‘Sanus and are released i the Buodtveam when simulate by 2 ‘pec siga. “amines ae water souble molecles dried fem ami aie Peptide and amine harmones 1 Hormones ae eynthaisd ad stored ingranuls inthe eytopasm atcols 2 Hormones a raloaced into the bods upon rouse nieve dct atoms (pee, RICE miata A Asomes SE ae ‘Stet coe er ae pee este enol and stimulates: Sic cores as “Target Hue cal How the diferent classes of hormones work Tablet Types of harmanes sero LUpiésluble Peptides and proters — Watersolble Pituitary gan, hypothalarus, pancreas, party land, thyus gland Adrenal lard, ovaries testes Amines ar ls stored in scretory ranles. Once these mone steleced inte the Dicer they ave a aget sue where ‘hey bind to eeptors on he sted surface of he target ce ‘eri hemes, produced bythe akeal land, ovaries cortetes, af ot red in endoine calls and are leced Ire they ae made, tric hormones re Ipi-sclble so ‘hey can ase rectly across to pasma mentzae ofthe target ‘el Onos inside the top, sttld hormones bind to thle ‘recaps forming 9 copes Ts complex then owes into the nacre tage genes unig pet expen ‘Steroid rmenes 1 Hermanes ae sythosiss are reveasea cect the oedstream Oestrogen testosterone “Gpnephne dopanine Ins foliclesimaating hormone, luting herone the follicular phase. The high levels of oestrogen stimulate the production of luteinisng hormone, LI (positive feedback). This is requised for the second phase, ovulation, in which the developing female gamete, ot oncyte is jected fram the ovary and migrates down the oviduct. Inthe final, luteal, phase: a corpus Tuteum develops which secretes mainly progesterone with some oestrogen. High progesterone concentrations inhibie the production of FSH and LH, In the absence of FSH and LH stimulation, the corpus Tuteum undergoes cll death and reabsorption. AS Febray 2013 ‘estrogen and progesterone concentrations fall, the negative feedback contol on FSH is removed, concentrations begin to rse, and the next menstrual, «cle is initiated. This eee begins at puberty and lass throughout the reproductive phase of every ‘woman until the onset ofthe menopause Ageing and the menopause The menopause is the stage in a woman life when her avariee stop producing gimetes and she is ro longer fertile. The menopause occurs because the ovaries no longer respond to FSI and LI 31i il { a — Lutenising hrmene (4) — Folicestinusti homere SH Pui hormones | } | [rots pase —e | ¢— Lea phase —e IVE E EEE era ee eee eres Tiel Figure2_ Hormona regulation ofthe menstrusl cyte, There ee thre dst pshoses. (1) The elclr phase is characterised by increasing levels of Uihich results in maturation af ovarian follicles, which n turn produce 0 ere levels peak atthe end ofthe phase. (2) Ovulation occurs duet high ‘jection ofan oocyte fom the over. (3) The teal phase is characterised bythe [duction of corpus luteum, wich secretes hgh level of progesterone en, w y etapa ge | ay se a ‘Menopausal : Ismet. ae é Fa * > 3 eheas Figure3_Mecn levels of ovrian hormones as women age Table 2 inceared health isk ascocated with the menopause Brain Strole, Alem’ ease east Breast cance snr ncontnence released from the pituitary gland, even though they continue to be released througout her ie. Lack ‘of ovulation results in reduced concentrations of ‘culating oestrogen and progesterone, Oestrogen ‘concentrations ustally begin fll fom around 35, yearsof age However, the most pronounced changes ‘cur around the menopause (ee Figure 3 ts the fll n these hotmones that gives rise to the characteristic symptoms of the menopause irregular menstruation, night seas, hot flushes, vaginal dryness. The average age of menopause is 51 — so women now lve the last thid oftheir lives with love oestrogen concentrations, resulting in increased risk of developing several chronic diseases (se Table 2). For eemple, the menopause is closely associated with an increased risk of developing osteoporosis — a reduction in bone strength leading to higher chance of fractures, Reduced concentrations of oestrogen result in increased bone reabsorption and decrease levels of new bone being deposited, which ultimately result in lower bone density. Hormone replacement therapy Women can be preseribed hormone replacement therapy (HRT) 1 alleviate the sympioms of menopause and reduce the risk of developing chron diseases, HRT ean be taken a8 3 combined estrogen-progesterone therapy or as an Bilegil Scones Reijestiogen-only therapy (for women who have had a hysterectomy), and can be administered by table, patch or implant. HRT can prevent osteoporosis by reducing bone loss and delay skin ageing. in post ‘menopausal women. Two large-scale studies (the Women's Health Initiative, WHI, and the Milion Women Study, MWS) looked atthe effect of HRT on the health of postmenopausal women, The WHI ‘eas conducted in the USA on more than 160000 volunteers between the ages of 50 and 79. These volunteers were randomly given either a placebo for HRT, The study was due to end in 2005 bat was terminated prematurely in 2002 when i¢was found that che HRT group hat! slighty increased risk of developing breast cance, stoke and coronary heart. Aisease compared with the placebo cont! geoup. “The MMS was conducted in the UK on more than 1 million postmenopausal women aged over 50 ‘This study confirmed findings from the WHT of an increased sk of stoke, breast cancer and coronary heart disease in women prescribed HRT compared with those who were taking a placebo. This study lho confirmed an increased risk of uterine cancer in women prescribed oestrogen-only HRT. After the publiation of these studies and the extensive media publicy tha followed, the number fof HRT prescriptions declined dramatically (see Figure) However, when the data werereanalysed, ‘aking into acount the length of time women were postmenopause before they started treatment, it was clear that women who began taking HRT ound the onset of menopause Wete ata decewed tisk of heart disease, These new findings have highlighted the potential difference of aking HRT avaiferent times during menopause. The reasons for thisae till unclear and ave the subject of much favestgation Hormones and wound healing ‘As people age, they have an increased risk of developing wounds that fail 10 heal properly — ‘onic wounds (se Figure 5). These wounds lead to pain, reduced mobility and social elation, Wis estimated that Lin 20 eldely people wll develop a ‘luoaie wound atsome point in their lifetime. Thre ae tree main types of chronic wound: pressure ulers, usually found in the pelvic region venous ulcers, common in the lower part ofthe leg diabetic fot ulcers, cause by an inability wo feel pain resulting in damage to tissues in the foot Chronic wounds have a major impact on the NUS, with annual treatment costs estimated 2 cover £3 billion. Currently, there are no effective ‘One ofthe main reasons that these wounds heal sodowly isthe decrease in oestrogen concentrations fin elderly men and wore, rather than age ite Febray 2013 ee categories Prevalence of HRTiper 1000 women 8 8 20002001 200220032004 2005 2006 Figure 4. umber of Hitt prescriptions. This graph shows thatthe numberof HRT resciptions fell dramatically after the publication of two studies the Vimen's Heath native in 2002 andthe Million Women Study 2003), This decrease was particularly pronounced in women aged 50-59 yeas, whichis the average age of tromen eneriog menopause and therefore at most rick of developing menopausal symptoms. txamples of chrane wounds (iaeti foot Figures Ir patients ate given HRT w increase the levels of estrogen citculating around the bods, healing is acelerated and these patients do not develop chronic wounds, Recent studies have shown that 33Encems bems Hien ceseegen I Low cestogen — ier cestczin | tow cestocen FF sien oestogen | Lowcstrozen mmatary ale lene ° ocd wes i Blood esses ' ‘Gestogen promotes cali inthe top _nflamnatry els. eased iro the Foyblest els depest tix lef shin (epidermal ea) to ound ofa rom blad esa in the skin (ation aes aos safe to be ale Iovecverthesuracect the wund, Thess Inferatyeals release faci hat —_‘orefom the skin stu). vtere pronotng naling. sly healing, Oestrogen reduces the number Oestrogen icreues he amber of Sf nnarmatry eels nd so prometes| ‘ola cll, resting n hight healing lel of mat Figure 6 Oestrogen promotes wound healing, The epidermis i the outer layer of cls inthe skin: the dermis the ayer of skin below ‘theepidermis. The let hand side ofeach panel shows what happens when oestrogen levels in the culation are high: the ight hand side shows what happens when oestrogen levels inthe circulation are low. 34 ees iy For gene nfrmaton about hormones and endocrine dscases got: www hormene.or9 For deat racing about the to large-scale research studies into the fects of HET go te ‘wureailionwomenstudy.org ‘rw tbh gob eeu! 3 Chronic disease A sess that develops gal ads erstent or sts a eng tne (months yeas Corpus luteum A tomporary endocrine ttre that ‘develops rom the vara fle and scretes high eve of prgestvone Endocrine sytem The syste in the body thats responsible fer the protuction of homens. Epidermis The ote layer) of celina muti exons, Homeostasis The maintenance of constant ena ontons Negative feedback A mechanism whereby the body can regate level of mores tough ther ov influence, when aomane eaces 2 high level ican inhibit further ‘cretion of tele oeyte immature egg el produced fam the ovary Placebo An noctive substance or preparation wed as 2 ‘onlin an experiment or fest fo determine the efictenes ola dus Positive feedback The opposite of negative feedback, ‘wher level of haxmane can hve pov effects othe “crton ofl ther hormones. SERMS Class f compounds that at though He oestosen rece | le) ec ee os. Seat ecee sere eer onl group, ice wih owes No weatment Treated wh osrogen ‘att 6 OH aes osrage eer mets ‘ne nergy vl 19 N29. org Semis iwesigated the effets of tamatifen on ‘waundheding in mice hat dd not have vais {rimiching the menopause). These mie were gen estroge or taonen ard the wounds were et to heal Vice wih intact ovaries were sed eon ‘helt wounds ware let untested Sr the same length ‘ftir. The 2 ofthe wounds was messed and ‘the eau and repented othe graph ss tmean wound ares standard eno of te mea, ‘Thee est show that amon poms wound healg in mice without ovaries to asimlor extent 25 cxstege. Bilegil Scones Reiestrogen can increave wound healing in several ays (ee Figure 6). For example, oestrogen promotes the migration of els inthe epidermis, ‘which helps to clove the wound reduces the numberof inflammatory cells that release harnfl factors ceases the production of ew skinky Abroblass However, because of the controversy surtounding the se of HRT, this tcatment is not asually preserbed for edeny patients suffering with chronie wounds. Instead, compounds called ‘selective estiogen receptor modulators’ — SERMS — ate being developed, Although these drugs ate being developed primarily o treat menopause astocated symptoms, they may als be useful forthe treatment ‘of etherhormone elated diseases, including chronic ‘wounds, SERMs bind to oestrogen receptors and promote cestrogen-tike beneficial effects such as reducing bone reabsorption during osteoporosis, without oestrogens detrimental side effect, such 235 increasing risk of breast cancer. Several SERMS fate in cutrent clinical use, including tamoxifen for the treatment of cancer (se Boxocien Sess Riv Vol. 24, No.1, pp. 38-1} and raloxifene for the prevention of exeopoross Interestingly, recent research has shown that SERMs can also improve wound healing in rats and mice to the same extent 2s oestiogen (eee Box 2}. Clinical tals are now being performed to determine whether SERMs can also promote wound healing in chronic wound patents. Laura Campbells final year PnD sucen Seer rar erate ene pepo * Hormones are chemical messenger released ar endocrine glands torque body functions. Hormone release thy controle by pstive and negative Feedback loops. A good example isthe system tring the female mers le n which ermanes ‘ucuate ona mathe. 1 As women oe the hormone levels sn, leading the menopese HRT sevetes symptoms of meropaine bots ao sscited with ightyineeosed risk of beveling condos uc a bres carer * Low oestrogen in postmenopausal waren Ineases the isk of developing aru of diseass, sh as ‘won wounds, stepoross, hear asease and stoke © rrent therapies exploting our knowledge of ‘estrogen signaling are bing developed to raet CBseses asada ith the menepaie. Clear focused revision fr your best possible grade + Understand he content ofeach unitwith nie sills you need 0 show + Practise for bett co Febray 2013 ) off voucher ut what a bing asain the exam andthe rads wit the help of examsty Cee Peer: 20% 35