CHAPTER I PREFACE

Infertility is defined as one year of reasonable frequency, unprotected intercourse during which pregnancy has not occurred1,2,3. Besides being a medical condition; infertility is a lowcontrol, chronic stressor with se ere long-lasting negati e social and psychological consequences. Infertility is potentially stigmati!ing which increase the se erity of stressor to couples who ha e not achie ed pregnancy. "or many couples, infertility causes a serious strain on their interpersonal relationship, as well as personal distress, reduced self-esteem, and loss of the meaning with life. #chie ing a pregnancy after assisted reproduction technology treatment is associated with increased mental well-being, but treatment failure is associated with increased le els of an$iety and depression2. %uccessful pregnancy requires a comple$ sequence of e ents including o ulation, o um pic&-up by a fallopian tube, fertili!ation, transport of a fertili!ed o um into the uterus, and implantation into a recepti e uterine ca ity. 'ith male infertility, sperm of adequate number and quality must be deposited at the cer i$ near the time of o ulation. (emembering these critical e ents can help direct a clinician to de elop an appropriate e aluation and treatment strategy. Infertility is a common condition, affecting 1) to 1* percent of reproducti e-aged couples. +f note, e en without treatment, appro$imately half of women will concei e in the second year of attempting1. +n a erage *,- .range /201,.3-2 of infertile couples in de eloped countries ha e sought medical ad ice2. In most cases of infertility, the etiology is distributed fairly equally among male factors, o arian dysfunction, and tubal factors. # smaller percentage of cases are attributed to endometriosis, uterine or cer ical factors, or other causes. In appro$imately one fifth of couples, the cause is uncertain and is referred to as une$plained infertility .3able 121,3.
1

It is well &nown that the reproducti e system is highly sensiti e to states of energy deficit, which li&ely pro ides an efficient mechanism to pre ent the energy demands of pregnancy and lactation under unfa orable conditions. #t the other e$treme, e$cessi e energy storage i.e. obesity also appears to interfere with proper regulation of the reproducti e system /. %erum leptin le els are significantly raised in infertile women as compared to fertile controls, irrespecti e of primary or secondary infertility*. #lthough leptin was originally thought to be e$clusi ely e$pressed in white adipose tissue, subsequent reports showed that leptin is e$pressed in se eral other areas, such as the hypothalamus, pituitary gland, fundic gastric epithelium, s&eletal muscle, syncytiotrophoblast, and mammary epithelium,. 4eptin at the lowest concentrations .1)-12 and 1)-11 mol2 produced a significant increase in 5n(6 release but it has diminishing effect at higher concentrations .1)-,mol2. 3he leptin receptor has also been identified in human anterior pituitary and pituitary tumors, and human fetal pituitary, suggesting that leptin may ha e direct effects at the le el of the pituitary. 4ow le el of leptin induce an increase in "%6 and 46 concentrations, but an e$periment showed that at higher le el it has an inhibitory effect on 46 and "%6 secretion from the pituitary. 3hus leptin may play a role in regulating hormones which control fertility/.

CHAPTER II INFERTILITY

2.1

Definition Infertility is defined as the inability of a couple to concei e after at least 1 year, with

regular coitus without contraception. 7rimary Infertility applies to those who ha e ne er concei ed. %econdary Infertility applies to those who wha e concei ed at some time in the past and with history of any pregnancy, including abortion or ectopic pregnancies. # 8ouple is said to be infertile if they ha e been trying to achie e a pregnancy for more than 1 year without success1.

2.2

Etiology Infertility can be due to either partner or both, # primary diagnosis of male factor is made

in appro$imately 2*- of cases. + ulatory dysfunction and tubal9peritoneal factors comprise the ma:ority of female factor infertility. 3he main causes of infertility include; male factor, o ulatory disorders, tubal in:ury, tubal bloc&age, paratubal adhesions, uterine factors, systemic conditions .infections or chronic disease, autoimmune conditions or chronic renal failure2, cer ical, immunologic factors, and une$plained factors1.

2.3

Female History #s with any medical condition, a thorough history and physical e$amination is critical,

for the female partner, questions should include a complete gynecologic history. %pecifically, questions regarding menstruation .frequency, duration, recent change in inter al or duration, hot flashes, and dysmenorrhea2, prior contracepti e use, coital frequency, and duration of infertility1. #lso a history of recurrent o arian cysts, endometriosis, leiomyomas, se$ually transmitted diseases, or pel ic inflammatory disease is pertinent. Because prior conception
3

indicates o ulation and a patent fallopian tube in the patient<s past, this history should be sought. 7regnancy complications such as miscarriage, preterm deli ery, retained placenta, chorioamnionitis, or fetal anomalies should be noted. # history of abnormal 7ap smears may be pertinent, particularly if a woman underwent cer ical coni!ation, which could impact cer ical mucus quality and cer ical competence. 'hen obtaining a medical history, it is critical to discuss coital history, including frequency and timing of intercourse. %ymptoms such as dyspareunia may point to endometriosis and a need for earlier laparoscopic e aluation of the female partner1. 3he medical history should be aimed at eliciting symptoms of hyperprolactinemia or thyroid disease. %ymptoms of androgen e$cess such as acne or hirsutism may point to the presence of polycystic o arian syndrome or much less commonly, congenital adrenal hyperplasia. 7rior chemotherapy or pel ic irradiation may suggest the presence of o arian failure. %urgical treatment of ruptured appendicitis or di erticulitis should raise suspicion for the presence of pel ic adhesi e disease or tubal obstruction or both1. # physical e$amination may pro ide many clues to the cause of infertility. =ital signs, height, and weight should be recorded. 6irsutism, alopecia, or acne indicates the need to measure androgen le els. 3he presence of acanthosis nigricans is consistent with insulin resistance associated with polycystic o arian syndrome or much less commonly, 8ushing syndrome. #dditionally, thyroid abnormalities should be noted. # pel ic e$am may be particularly informati e. Inability to place a speculum through the introitus may raise doubts about coital frequency. 3he agina should be moist and rugated, and the cer i$ should ha e a reasonable amount of mucus, both indicating adequate estrogen production. #n enlarged or irregularly shaped uterus may reflect leiomyomas, whereas a fi$ed uterus suggests the presence of pel ic scarring due to endometriosis or prior pel ic infection1.

CHAPTER III LEPTIN PHY I!L!"Y

3.1

Le#tin 4eptin is a protein hormone with important effects in regulating body weight,

metabolism, and reproducti e function. 3he protein is appro$imately 1, &>a in mass and encoded by the obese .ob2 gen?@. 4eptin, disco ered through positional cloning 1* years ago is an adipocyte-secreted hormone with a &ey role in energy homeostasisA. 3.1.1 $iosynt%esis an& 'ir'(lation 4eptin is a 1,1 amino acid protein which belongs to the cyto&ine family 1). 6uman leptin gene is located on chromosome 111. It is manufactured primarily in the adipocytes of white adipose tissue, and the le el of circulating leptin is directly proportional to the total amount of fat in the body. In addition to white adipose tissue, the ma:or source of leptin, it can also be produced by brown adipose tissue, placenta .syncytiotrophoblasts2, o aries, s&eletal muscle, stomach .lower part of fundic glands2, mammary epithelial cells, bone marrow, pituitary, and li er. 4eptin play &ey role in food inta&e, energy balance, and adiposity as well as in immune and endocrine system. It acts as feedbac& loop to maintain the constant store of body fat12. 4eptin le els are pulsatile and follow a circadian rhythm, with highest le els between midnight and early morning and lowest le els in the early- to mid- afternoon . %pecifically, the concentration of circulating leptin may be up to 1*.,- higher during the night as compared to afternoon trough le els. 3he pulsatile characteristics of leptin secretion are similar in obese and lean indi iduals, e$cept the obese ha e higher pulse amplitudes. 4eptin concentration reflects the amount of energy stored in body fat. 8irculating leptin le els are directly proportional to the amount of body fat and fluctuate with acute changes in caloric inta&e. 3his system is especially sensiti e to energy depri ation. 'omen tend to ha e higher leptin le els than men, although women
5

e$perience a significant decline in the amount of circulating leptin after menopause. 3his se$ual dimorphism is largely independent of body mass inde$ .BBI2, and is due in part to differences in se$ hormones, fat mass, and body fat distribution. 'omen tend to accumulate body fat peripherally whereas men are prone to an abdominal or android distribution of fat. %ubcutaneous fat e$presses more leptin m(C# than omental fat, and this may partially e$plain the higher leptin concentrations in women compared to men. 6ormones and cyto&ines other than se$ steroids also affect leptin secretion but to a smaller degree .3able 2213. Ta)le 2. Fa'tors t%at reg(lates 'ir'(lating le#tin le*els13

Fa'tors #romoting le#tin se'retion ?$cess energy stored as fat .obesity2 + erfeeding

Fa'tors in%i)iting le#tin se'retion 4ow energy states with decreased fat stores .leannes2 "asting

5lucose 8athecolamines and adrenergic agonists Insulin 3hyroid hormones 5lucocorticoids 7ero$isome ?strogens Inflammatory 3umor cyto&ines, "actor including and 7roliferator-acti ated (eceptor- .77#(2 agonists Inflammatory cyto&ines, including

Cecrosis

Interleu&in-, .accute effect2

3umor Cecrosis "actor .prolonged effect2

>%ource from ; >ubuc 5, 7hinney %, %tern D, 6a el 7. 8hanges of serum leptin and endocrine and metabolic parameters after 1 days of energy restriction in men and women. Betab. 8lin. ?$p. 1AA@ ;/1 ./2; /2A03/.

8oncentrations of leptin in peritoneal fluid correlated significantly with BBI,,1/. 8irculating le els of this hormone are proportional to body fat mass 1*,1/. 3his strongly suggests that body mass may be one of the factors determining peritoneal-fluid leptin le els in endometriosis patients and not the endometriosis alone 1*. %ince leptin has also been reported to be e$pressed and produced by endometrial and endometriotic cells, this source of the peritoneal-fluid leptin may also be considered1*,1/. "urthermore, it has been found that leptin production may be stimulated by proinflammatory factors, and it is thus plausible that changes in peritoneal-fluid leptin concentrations may also directly or indirectly reflect an immune status of the patient1/. Boreo er, 3C" and I4-1 are &nown to increase leptin production 1*,1,. 3he increase in I4-1 and 3C"-a in 7" of women with endometriosis may be related to the present findings, gi en that these inflammatory cyto&ines can stimulate leptin secretion. Inflammatory cyto&ines ha e been reported to stimulate leptin secretion such that an increase in serum leptin concentrations is obser ed after the administration of I4-1 or 3C"-a in rodents. # positi e correlation between leptin le els and acti ation of the 3C"7

a system has also been found in humans with increased circulating concentrations of leptin obser ed during fe er and systemic inflammation. It has been demonstrated that leptin has a mar&ed and specific effect on 8>/E 3 lymphocyte responses and their cyto&ine profiles, pro iding further lin&s between leptin, inflammation, and immunity1*.

3.1.2

+e'%anism of a'tion 4eptin binds to leptin receptors .ObRs2 located throughout the central ner ous

system and se eral peripheral tissues. #t least si$ ariations or isoforms of the leptin receptor ha e been identified .ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf). 3hese isoforms ha e homologous e$tracellular domains but distinct intracellular domains, which ary by length and sequence due to alternati e m(C# splicing. 3he short isoforms ObRa and ObRc are thought to play important roles in transporting leptin across the blood0brain barrier .BBB2. 3he long leptin receptor isoform ObRb is primarily responsible for leptin signaling12. 3he long leptin receptor isoform is e$pressed abundantly in the hypothalamus and acti ates the Danus &inase signal transducer and acti ator of trascription .D#F-%3#32 system to alter the e$pression of hypothalamic neuropeptides. 3his functional leptin receptor ObRb, e$pressed in se eral organs, is strongly e$pressed throughout the central ner ous system but particularly in the hypothalamus, where it regulates energy homeostasis and neuroendocrine function described further below. In the db/db mouse model, the ObRb is dysfunctional, resulting in obesity and the metabolic syndrome13. #cti ation of ObRb sets off a cascade of se eral signal transduction pathways of which the best studied pathway is the Danus &inase 29signal transducer and acti ator of transcription 3 .D#F29%3#332 pathway. %3#33 has been shown to mediate the transcription of se eral genes that affect a number of cellular processes. 4eptin controls energy homeostasis and body weight primarily by acti ating ObRb in the hypothalamus. 3he ObRb acti ate numerous D#F29%3#33-dependent and -independent signaling pathways that act in coordination as a networ& to fully mediate leptin<s action. 3he acti ation of indi idual pathways in the leptin signaling networ& appears to be
8

differentially regulated in discrete subpopulations of ObRb-e$pressing neurons. 3hese pathways are also li&ely to be regulated by arious other hormonal, neuronal, and metabolic signals that cross-tal& with leptin. 6ence, it is important to fully determine whether and how positi e and negati e regulators of ObRb signaling, metabolic state, and9or neuronal acti ity regulate leptin signaling networ&s in a cell9tissue type-specific manner and how acti ation of these signaling pathways mediates leptin<s effects in humans13.

CHAPTER I, LEPTIN !N REPR!D-CTI,E Y TE+ AND FERTILITY

..1

Le#tin/s effe't on re#ro&('ti*e system # component of the lipostat theory years ago was the hypothesis that some biochemical

signal from adipose tissue ser es as the feedbac& regulator to tell the brain the status of peripheral body nutrition. 3his signal is now understood to be leptin, which feeds bac& to the arcuate nucleus in the regulation of neuropeptide G .C7G2, as the most important molecule in ol ed in appetite regulation. 3he arcuate nucleus is also the site of &ey reproducti e control as the origin of 5n(6. ?arly studies tested the hypothesis that leptin may be in ol ed in both hypothalamic and pituitary gonadotropin regulation. Bc8ann and his colleagues incubated hemianterior pituitaries of adult male rats with increasing concentrations of leptin for 3 hours and obser ed a dose dependent stimulation of "%6 and 46 release. / 7rolactin secretion was also increased in a dose dependent manner, but only at higher leptin concentrations. 3hese studies

were the first to demonstrate a direct in itro effect of leptin on pituitary 46, "%6, and prolactin secretion11. ..1.1 Le#tin an& 'entral reg(lation of t%e gona&otro#in0gona&al a1is 3he role of leptin in regulating reproduction and the hypothalamic-pituitarygonadal .6752 a$is is a crucial, permissi e one. /,1@ 8ongenital leptin deficiency and9or loss of leptin function due to leptin or leptin receptor mutations leads to hypogonadotropic hypogonadism with low le els of follicle stimulating hormone and luteini!ing hormone, complete loss of luteini!ing hormone pulsatility, lac& of pubertal growth spurt, reduced e$pression of secondary se$ual characteristics, and primary amenorrhea.1@ 3he clinical features of hypothalamic hypogonadism and associated disturbances can be restored by leptin administration in replacement doses. +n the other end of the spectrum, ele ated leptin le els due to increased body fat mass associated with obesity may also ha e an inhibitory effect on the 657 a$is. 4eptin may thus ser e as a signal to con ey information to the reproducti e system that the amount of energy stored in the body as fat is adequate not only for the sur i al of the indi idual but also for carrying a pregnancy to term. Because a certain threshold le el of energy and body fat mass, which may ary from indi idual to indi idual, seems to be necessary for the onset of puberty and normal fertility, leptin has been proposed to be a permissi e signal, which can acti ate the reproducti e a$is and maintain normal reproducti e function by con eying needed information on a ailable energy reser es in the adipose tissue. Boreo er, in states of secondary failure of the 675 a$is associated with loss of fat mass, such as in e$ercise-induced amenorrhea or anore$ia ner osa, e$ogenously administered leptin may fully normali!e the function of the 675 a$is.1@ %ome of the reproducti e dysfunction resulting from states of leptin deficiency and e$cess, leptin appears to play a &ey role in proper functioning of the reproducti e system. It is well &nown that the reproducti e system is highly sensiti e to states of energy deficit, which li&ely pro ides an efficient mechanism to pre ent the energy demands of pregnancy and lactation under unfa orable conditions. #t the other e$treme, e$cessi e energy storage i.e. obesity also appears to interfere with proper regulation of
10

the reproducti e system. %ince leptin con eys a signal of the amount of energy stores to the brain, a logical hypothesis would be that leptin is the lin& between energy reser es and neural networ&s controlling reproduction. (ecent studies ha e shed more light on how leptin may con ey this signal to the reproducti e a$is ."igure 12. In healthy women who underwent frequent blood sampling e ery 1 minutes for 2/ hours, the pulsatile release of leptin showed a significant pattern synchrony with serum 46 and estradiol le els, especially at night when leptin le els reached their pea&. 3his suggested that leptin may regulate the physiologic le els and rhythmicity of reproducti e hormones. 3a&en together, this e idence suggests that either leptin regulates 46 release/.

Fig(re 1. Le#tin an& t%e %y#ot%alami'0#it(itary reg(lation of t%e gona&otro#in0 gona&al a1is..

11

4eptin is secreted from adipose tissue and induces gonadotropin secretion from the hypothalamus and pituitary as well as gonadal steroid output from the gonads. %olid arrows indicate established interactions whereas dotted arrows indicate potential interactions. IEJor I-J signs indicate stimulatory or inhibitory effects, respecti ely, and both together indicate e idence for both stimulatory and inhibitory effects. "%6, follicle stimulating hormone; 5n(6, gonadotropin stimulating hormone; 46, luteini!ing hormones. %ource from; . 48 Dean, %B 8hristos. 4eptin and the hypothalamic-pituitary regulation of the gonadotropin gonadal a$is. Fluwer #cademic 7ublishers 2))1; /; @1-A2.

..1.2

Le#tin an& t%e Hy#ot%alam(s # number of studies ha e been performed which pro ide e idence that leptin may

influence gonadotropin release at the le el of the hypothalamus ."igure 22. 4eptin administered peripherally to adult o ariectomi!ed estrogen-treated rats during a /@-hour fast pre ented the suppression of 46 pulse frequency that occurs during fasting, pro iding e idence that leptin may regulate 5n(6 since changes of 46 pulse frequency reflect timing of 5n(6 release. 3o more directly in estigate leptinHs effect at the hypothalamic le el, Gu et al. performed an e$periment in which pro ed that leptin at the lowest concentrations .1)-12 and 1)-11 mol2 produced a significant increase in 5n(6 release within 3) to ,) minutes, an effect that was not seen at higher concentrations .1) ,

mol2 and was in fact associated with a significant decrease in 5n(6 compared to

controls. "urther e$periments suggested that this effect was mediated by nitric o$ide since the stimulatory effect of leptin on 5n(6 release was completely inhibited by a competiti e inhibitor of nitric o$ide synthase/.

..1.3

Le#tin an& t%e #it(itary

12

3he leptin receptor has also been identified in human anterior pituitary and pituitary tumors, and human fetal pituitary, suggesting that leptin may ha e direct effects atthe le el of the pituitary ."igure 1213. Ksing immunoelectron microscopy and immunocytochemistry, =idal et al, demonstrated that leptin is found in the same secretory granules as adenohypophysial hormones, suggesting that leptin is secreted concomitantly with these hormones and that leptin release may be under hypothalamic control/. Gu et al. in estigated leptinHs effect on the pituitary by incubating anterior pituitaries of adult male rats with leptin for 3 hours and found that leptin produced a dose-related increase in follicle stimulating hormone ."%62 and 46 release, with ma$imal effects at 1)-A and 1)-11 mol concentrations of leptin, respecti ely. 4eptin was nearly as effecti e as 5n(6 in releasing "%6 and 46. 3ena-%empere et al performed an e$perimentand found that leptin at 1)-A .but not 1)-1 or 1)-@2 mol concentration had an inhibitory effect on 46 and "%6 secretion from the pituitary, suggesting that leptinHs effects on hypotalamic and pituitary secretion may be different base on the leptin concentration. 4eptin with a small . less than 1)-A mol2 concentration will stimulate the e$cretion of 5n(6, 46 and "%6 but leptin with the concentration higer than 1) -A mol will inhibits this e$cretion. "or the conclusions, this effect of e$cess leptin concentration may cause the disturbance in someone reproducti e function, menstruation cycle and fertility/.
Fig(re 2. Le#tin2s a'tion in t%e )rain &(ring states of energy e1'ess an& energy &efi'ien'y13.

13

>uring states of leptin and energy e$cess, leptin<s access to the hypothalamus and other brain areas is impaired and leptin<s action is blunted. In states of leptin and energy deficiency, neuropeptides that are normally inhibited by leptin are ele ated .E2 and neuropeptides stimulated by leptin are suppressed .-2. # change in the concentrations of these neuropeptides leads to alterations in neuroendocrine function and energy homeostasis. #lterations in leptin le els may also affect the hedonic aspects of feeding beha ior. 3he role of leptin in the brain is discussed in greater detail in the te$t. A))re*iations3 ACTH, adrenocorticotropic hormone; AgRP, agouti-related peptide; ARC, arcuate nucleus; $DNF, brain-deri ed neurotrophic factor; CART, cocaine- and amphetamineregulated transcript; CC4, cholecysto&inin; CRH, corticotropin-releasing hormone; F H, follicle-stimulating hormone; "H, growth hormone; "LP01, glucagon-li&e peptide 1; "nRH, gonadotropin-releasing hormone; I"F01, insulin-li&e growth factor 1; LH, luteini!ing hormone; LHA, lateral hypothalamic area; +CH, melanin-concentrating hormone; NPY, neuropeptide G; N T, nucleus of the solitary tract; P!, preoptic area; P!+C, proopiomelanocortin; P,N, para entricular nucleus; area. %ource from; >ubuc 5, 7hinney %, %tern D, 6a el 7. 8hanges of serum leptin and endocrine and metabolic parameters after 1 days of energy restriction in men and women. Betab. 8lin. ?$p. 1AA@ ;/1 ./2; /2A03/. N, substantia nigra; TRH, thyrotropin-releasing hormone; T H, thyrotropin-stimulating hormone; ,+H, entromedial hypothalamus; ,TA, entral tegmental

..1..

Le#tin an& menstr(al 'y'le In mice, leptin is also required for male and female fertility. 4eptin has a lesser

effect in humans. In mammals such as humans, o ulatory cycles in females are lin&ed to energy balance .positi e or negati e depending on whether a female is losing or gaining weight2 and energy flu$ .how much energy is consumed and e$pended2 much more than
14

energy status .fat le els2. 'hen energy balance is highly negati e .meaning that a woman is star ing2 or energy flu$ is ery high .meaning that a woman is e$ercising at e$treme le els, but still consuming enough calories2, the o arian cycle stops and females stop menstruating. +nly if a female has an e$tremely low body fat percentage does energy status affect menstruation. %ome studies ha e indicated that leptin le els outside an ideal range can ha e a negati e effect on egg quality and outcome during in fertili!ationA,11. # study with fi e sampling windows, obser ed a pea& in serum leptin in the late luteal phase with a drop in the early follicular phase and a return to higher le els in the ne$t luteal phase. %imilar results were also reported by others. 'hen samples were obtained e ery 1-2 days throughout the menstrual cycle, plasma leptin was seen to increase from the early follicular phase to pea& le els at the midluteal phase, returning to baseline by menses. 8learly, a greater sampling frequency results in a better descripti e picture of leptin changes during the cycle. >espite minor differences, the luteal phase, either mid or late, is reported to be the period of pea& serum leptin concentrations, with some studies also nothing an increase during the late follicular phase/. 3ataranni et al. did not find serum leptin changes o er the course of the menstrual cycle and suggested that body fat content may be a more important determinant of serum leptin le els than cycle stage. In our own studies, which featured daily sampling, we demonstrated changes in serum leptin that were related to the stage of the cycle in normal weight women, with leptin le els increasing during follicular de elopment and a secondary increase in the luteal phase. In obese women who continued to e$perience o ulatory cycles, at best an infrequent occurrence, there was no pattern of leptin associated with cycle stage, but rather leptin le els were mar&edly ele ated abo e those in normal o ulatory cycles. In this group of obese women, luteal phase progesterone le els were11. itro

..2

Le#tin/s effe't on fertility

15

#s leptin e$erts significant effects on female reproducti e system, it might be related to infertility. 3he present study was designed to in estigate the leptin concentrations in peritoneal fluid and serum samples of women diagnosed with different etiologies of primary infertility. 3ubal factor, polycystic o arian syndrome .78+%2, and endometriosis were determined as three ma:or causes of infertility and the remaining sub:ects for who any alid pathology could not be established were designated under une$plained infertility after laparoscopic e aluation,. 7reo ulatory follicles released leptin into the peritoneal fluid and suggested that 78+% diminished leptin le els by interrupting the de elopment of follicles. Bant!oros et al. supported the former finding by showing that amenorrhoeic and oligomenorrheic women had lower le els of leptin in peritoneal fluid. 4eptin is e$clusi ely produced by adipose tissue so plasma leptin le els directly correlate with BBI. #s 78+% tends to cause weight gain or obesity, it might be related to ele ated concentrations of leptin in plasma. In the present study, 78+% sub:ects were also found to ha e significantly higher BBI alues, and rele antly ele ated plasma leptin le els,. %erum leptin le els are significantly raised in infertile women as compared to fertile controls, irrespecti e of primary or secondary infertility. Body weight and BBI were also found to be increase in infertility women as compared to fertile controls. It has been established that leptin is essential for normal reproduction in animal and humans. But, at the same time many studies confrimed the inhibitory effect of hyperleptinemian reproduction. +besity associated hyperleptinemia, gradually induces central leptin resistance, increase hypothalamic neuropeptide G-ergic tone, and ultimately causes hypothalamic hypogonadism. 6igher le els of leptin in the peritoneal fluid in patients with endometriosis, which is a ma:or cause of primary infertility. 6igh leptin le els in the o ary may interfere with de elopment of dominant follicles and oocytes maturation. 3his indicates that ele ated leptin le els may be able to e$ert a direct inhibitory effect on o arian function. + erweight accompanied by hyperleptinemia is generally associated with infertility in females. Increased leptin le els as a result of o erweight may deregulate the hypothalamic-pituitary-gonadal system, leading to reproducti e dysfunction, including infertility/,*.

16

CHAPTER , TREAT+ENT F!R LEPTIN A$N!R+ALITY

5.1

Treatment for states of le#tin &efi'ien'y Cowaday, many reasearchers ha e found a way to treat the states of leptin deficieny. +ne

of the most effecti e treatment for leptin deficiency is to gi e the leptin replacement therapy for the patient. Da or et al.1@, ha e reported the long-term effects of leptin replacement in a cohort studies for fifteen patients with generali!ed lipodystrophy that induced the states of leptin deficiency in this patients. 3his fifteen patients were treated with twice-daily recombinant methionyl human leptin .r-met6u4eptin2, which is a leptin replacement therapy, for 12 months.
17

Bost female patients from this fifteen patients, resumed, and sustained normal menses following initiation of r-met6u4eptin consistent with normali!ation of their gonadotropin a$is 1@. 3he clinical features of hypothalamic hypogonadism and associated disturbances can be restored by leptin administration in replacement doses1A. "urthermore, both thyroid and adrenal functions were normal at baseline and did not change with r-met6u4eptin therapy in this study1@. 3reatment for this deficiency state of leptin was not only good for the reproducti e function, but also ha e some good effects on fat and glycemic control. # trial was done in patients with se ere hypertriglyceridemia which is treated with (-met6u4eptin. 3he result of this trial was also ery effecti e, their trial led to a ,3- reduction in mean triglycerides. 3he most dramatic reductions of triglycerides were seen after / months but increased thereafter due to noncompliance. %ignificant reductions were pre iously seen in intramyocellular fat content. #ll patients in the trial had diabetes before r-met6u4eptin therapy and administration of leptin had led to a significant reductions in fasting plasma glucose. Impro ement in insulin sensiti ity was further reflected in diabetic management during the course of r-met6u4eptin therapy. #fter r-met6u4eptin therapy, , of A patients with generali!ed lipodystrophy do not need insulin to achie e glycemic control. +nly two patients still need an insulin but were able to decrease their mean dose by ,*-. 4i&ewise, si$ of eight patients were able to discontinue oral antihyperglycemic agents .primarily metformin2 during r-met6u4eptin therapy1@. 5.2 Treatment for states of le#tin e1'ess It is well established that obesity is associated with hyperleptinemia, which may cause either leptin tolerance or leptin receptor resistance. >espite initial hopes, placebo-controlled trials in obese sub:ects o er periods ranging up to 2/ wee&s ha e clinically shown no impressi e weight loss in leptin-treated sub:ects compared with placebo-treated controls. 5i en the initial high e$pectations for r-met6u4eptin as a potential treatment for obesity and the impressi e results seen in leptin-deficient patients, but , results in sub:ects with ariety obesity ha e thus been considered to be disappointing. Bore recent e idence indicates, howe er, that coadministration of leptin with medications that could sensiti!e the body to leptinHs actions could possibly pro ide better weight loss outcomes 1A. 3he primarily way to deal with the leptin e$cess

18

is to reduce the main source of leptin which is body fat. %ome ways of decreasing body fat is e$cercising or fasting. %ome trial ha e pro ed there were some incidence of e$ercise-induced amenorrhea or anore$ia ner osa that related to reduction of fat mass that will decrease leptin le el1@.

CHAPTER ,I C!NCL- I!N

Cot only infertility is a distressing medical problem but also has a negati e social and psychological consequences for the couples2. Incidence is quite common, ranging from 1) to 1* percent of reproducti e-aged couples1. Bost infertile couples in de eloped countries will sought medical ad ice2. In most cases of infertility, the etiology is distributed fairly equally among male factors, o arian dysfunction, and tubal factors1,3. 4eptin is a protein hormone with important effects in regulating body weight, metabolism, and reproducti e function@. In addition to white adipose tissue, the ma:or source of leptin, it can also be produced by brown adipose tissue, placenta, o aries, s&eletal muscle, stomach, mammary epithelial cells, bone marrow, pituitary, and li er 12. 8irculating le els of leptin are proportional to body fat mass 1*,1/ and a fraction of this hormone can be found in
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peritoneal fluid,,1/. 4eptin is also ele ated by inflammatory cyto&ines such as 3C" and I4-1 which demonstrates itHs correlation with immunity1*. (eproducti e system is highly sensiti e to states of energy deficit, which li&ely pro ides an efficient mechanism to pre ent the energy demands of pregnancy and lactation under unfa orable conditions. 4eptin con eys a signal of the amount of energy stores to the brain which in turn regulates reproducti e hormones secretion by pituitary /. #nimal e$periments ha e shown that leptin cause inhibitory effect on early follicular de elopment * and there is fa orable range of le els of leptin which promotes reproduction. # concentration that is too low or too high will impair reproducti e hormones secretion/. %tates of leptin deficiency and leptin e$cess both disturb the reproducti e hormones production/. 4eptin replacement therapy is effecti e for patients with leptin deficiency 1@. #fter administration of r-met6u4eptin most patient resume their normal menses in correlation with normali!ation of gonadotropin-a$is. Benefits of r-met6u4eptin also shown in its ability to reduce triglyceride le el, decrease fasting plasma glucose, and impro e insulin sensiti ity 1A. But the result of r-met6u4eptin therapy in patients with leptin e$cess had been disappointing. 3he only &nown method to decrease leptin concentration is to reduce the body fat which is the source of leptin production. %ome ways of decreasing body fat is e$cercising or fasting1@.

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