PROSTAGLANDINS AND BIOCHEMISTRY OF FERTILITY A TERM PARER ON MEDICAL BIOCHEMISTRY (BCHM 813)

BY GROUP ONE MEMBERS: NWOSU, OLUCHI EKWUTOSI ADEJO, BLESSING ENE ALIYU, NAFISATU ABDULWAHAB, RABIAT ADAMUDE, FATIMA AMIN DINGWOKE, EMEKA MSC/SCIEN/00140/2010-2011 MSC/SCIEN/00319/2010-2011 MSC/SCIEN/00739/2010-2011 MSC/SCIEN/00903/2010-2011 MSC/SCIEN/13892/2010-2011 MSC/SCIEN/01335/2010-2011

SUBMITTED TO DR. A.I UMAR DEPARTMEMT OF BIOCHEMISTRY AHMADU BELLO UNIVERSITY, ZARIA

AUGUST, 2011

TABLE OF CONTENT TITLE PAGE ABSTRACT 1.0 INTRODUCTION PROSTAGLANDINS NOMENCLATURE TYPES OF PROSTAGLANDINS STRUCTURE OF PROSTAGLANDINS FERTILITY RATES FOR THE SYSTEMS BASED ON PROSTAGLANDINS 2.1 2.2 2.3 2.4 2.5 3.0 MECHANISM OF ACTION OF PROSTAGLANDINS ROLE OF PROSTAGLANDINS IN GONADOTROPIN SECRETION OVULATION AND PROSTAGLANDINS PROSTAGLANDINS IN THE UTERUS PROSTAGLANDINS AND PARTURITION CONCLUSION

ABSTRACT Prostaglandins are hormone-like substances that exhibit a wide range of biological effects, and their actions are among the most varied of any naturally occurring compounds. Despite this observation, this group of lipids displays a marked structure-activity specificity, which is determined mainly by cyclopentanone ring substitutions and the degree of unsaturation of the prostanoic acid side chains. The cellular response to prostaglandins is mediated by their interaction with plasma membrane receptors. Even though PGs mediate many steps of inflammation, they also have a wide range of physiological functions, including essential steps in the female reproductive cycle, regulation of vascular tone, platelet function, and fertility. They also play key roles as inflammatory mediators and modulators of tumor biology. Although they are technically hormones, they are rarely classified as such.

CHAPTER ONE 1.0 1.1 INTRODUCTION PROSTAGLANDINS

The name prostaglandin was derived from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler and independently by M.W. Goldblatt, It was believed to be part of the prostatic secretions in fact, prostaglandins are produced by the seminal vesicles. It was later shown that many other tissues secrete prostaglandins for various functions. The first total synthesis of prostaglandin F2 and prostaglandin E2 were reported by E. J. Corey in 1969 an achievement for which he was awarded the Japan Prize in 1989 (Wikipedia). Prostaglandins have been proposed as mediators of more physiological responses than any biological substance yet described except cyclic adenosine monophosphate (cAMP). They have been implicated in reproductive processes both in male and female, being present in most tissues of the reproductive tract. In addition, most tissues associated with reproduction can readily biosynthesize prostaglandins in response to the appropriate stimuli, in production within the female mammal alone, physiological roles of the prostaglandins have been indicated in menstruation, dysmenorrhea, oviduct motility, gamete transport, regression of the corpus luteum, biosynthesis of ovarian steroids and parturition (Pharriss and Jane, 1974). Currently, three classes of prostaglandins are recognized, and these are categorized on the basis of the number of double bonds present within the prostaglandin molecule and on the fatty acid from which they are derived. Thus, prostaglandins of the 1 series have one double bond and are derived from dihomo--linolenic acid, those of the 2 series have two double

bonds and are derived from arachidonic acid, and those of the 3 series have three double bonds and are derived from eicosapentaenoic acid (Zreik and Behrman, 2008).

1.2

NOMENCLATURE OF PROSTAGLANDINS

Prostaglandins are represented by PG, followed by appropriate alphabet e.g., A, B, E and F with numerical subscripts to denote specific number of each class. Further subdivision utilizes or . The numerical subscripts denote the number of double bonds in the extra ring structure. after the numerical subscripts denotes the placing of the hydroxyl group (books.google.com) 1.3 TYPES OF PROSTAGLANDINS

The following is a comparison of different types of prostaglandin, prostacyclin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F2 (PGF2). TYPES PGI2 IP EP1 PGE2 EP2 EP3 RECEPTORS Vasodilation. Inhibit platelet aggregation. bronchoconstriction GI tract smooth muscle contraction GI tract smooth muscle relaxation Uterus contraction (when pregnant). Smooth muscle contraction. Lipolysis inhibition. Uterus contraction. PGF2 FP Bronchoconstriction. FUNCTIONS

1.4

STRUCTURE OF PROSTAGLANDINS

Prostaglandins are unsaturated carboxylic acids, consisting of a 20 carbon skeleton that also contains a five member ring and are based upon the fatty acid, arachidonic acid. There are a variety of structures one, two, or three double bonds. On the five member ring there may also be double bonds, a ketone, or alcohol groups.

CHAPTER TWO 2.0 FERTILITY RATES FOR THE SYSTEMS BASED ON PROSTAGLANDINS

It is generally accepted that fertility, in terms of conception rates, of the cyclic heifer after prostaglandin treatment is not impaired compared with untreated control animals inseminated at a natural oestrus. However, conception rate in lactating dairy cows following prostaglandin treatment has been inconsistent and is sometimes lower than in control cows inseminated at a natural oestrus. The inconsistency in results between studies has been attributed to differences in management conditions, oestrous detection efficiency and accuracy. As mentioned by Diskin et al., (2002) it has also been suggested that the lower fertility in prostaglandin treated cows may be due to the fact that a high proportion of cows are inseminated after having a short luteal phase. There is evidence for both heifers and cows that animals injected with prostaglandin at the late stage of the luteal phase have both a greater oestrous response and a higher conception rate than animals treated in the early and or midluteal stages (Nebel et al., 1998; Diskin et al., 2002). 2.1 MECHANISM OF ACTION OF PROSTAGLANDINS

Prostaglandins exhibit a wide range of biological effects and their actions are among the most varied of any naturally occurring compounds. Despite this observation, this group of lipids displays a marked structure-activity specificity, which is determined mainly by cyclopentanone ring substitutions and the degree of unsaturation of the prostanoic acid side chains.

Prostaglandins are rapidly degraded and have such short half-lives that their functions are usually considered to be limited to actions on nearby cells. Prostaglandins seem to act through two separate mechanisms. Secreted prostaglandins bind to specific cell surface Gprotein coupled receptors, and generally increase cAMP levels. Prostaglandins may also bind to nuclear receptors and alter gene transcription. An injection of prostaglandin will induce regression of the corpus luteum ending the luteal phase. A new follicular phase begins and the animal will come into oestrus and ovulate. Fertility at the induced oestrus is similar to that of a natural oestrus. 2.2 ROLE OF PROSTAGLANDINS IN GONADOTROPIN SECRETION

Physiological role of prostaglandins in the regulation of gonadotropin-releasing hormone (GnRH) secretion have been published (Behrman, 1979). Prostaglandins particularly PGE 2, exert stimulatory influences on gonadotropin release, an effect that appears to be mediated by an action at the level of the hypothalamus. PGE2 has been shown to stimulate the release of GnRH from the hypothalamus, and pre-treatment of animals with antisera to neutralize endogeneous GnRH prevents the PGE2-induced release of LH (Robinson and Vane, 1974). 2.3 OVULATION AND PROSTAGLANDINS

Prostaglandins are involved in many aspects of reproduction, from ovulation and fertilization through to labour. They are produced in the foetus and in the placenta as well as in other reproductive tissues. In particular, the synthesis of PGE 2 and PGF2 is increased appreciably during labour, and these prostaglandins are in fact used as drugs to induce labour. Prostaglandins were involved in the ovarian follicular rupture process. This was strengthened by the finding that intra-ovarian injection of PGF2 antiserum also inhibited ovulation (Armstrong et al., 1974). There is now a substantial amount of evidence indicating that

follicular prostaglandin formation is enhanced during ovulation and that this elevation is dependent on gonadotropins (Marsh et al., 1974). LH appears to be the dominant physiologic pituitary gonadotropin responsible for the induction of ovulation, and it seems likely that the effects of LH on follicular rupture may be mediated by leukocytes that secrete proteolytic enzymes, oxygen radicals, and prostaglandins. Indomethacin, for instance, will block ovulation normally induced by large doses of human chorionic gonadotropin in vivo. Prostaglandins may mediate the stimulatory effects of LH on ovulatory enzymes, such as protease or collagenase (Beers, 1975) It seems that the only time ovarian PGF2 production is enhanced in the human menstrual cycle is shortly after ovulation (Swanston, 1977)A possible mechanism of prostaglandin action in follicular rupture is shown below.

MECHANISM OF PROSTAGLANDIN ACTION IN FOLLICULAR RUPTURE SOURCE: Behrman 1979. 2.4 PROSTAGLANDINS IN THE UTERUS

Various prostaglandins are also produced in the uterine cervix, and receptor sites for both PGE and PGF are present in the cervix.69 The increased production of prostaglandins, or their local administration, is associated with cervical ripening in pregnant women (Goldberg and Ramwell, 1975) Prostaglandins are required for ovulation, regression of the corpus luteum (i.e., ending the monthly menstrual cycle), sperm motility, immune interaction, contraction of the uterus at birth and menstrual cramps. Endometrial implants and the endometrium of the uterus are the richest source of prostaglandin production in the body. However, the problem with endometrial implants includes:
I) Prostaglandins are released into the abdomen instead of inside the womb. II) Prostaglandins release by the implants seems to be out of phase with their release by the

uterus.
III) Prostaglandins are produced at the wrong time sending the wrong message

For instance, there is a normal surge in prostaglandin F production at the end of the menstrual cycle, causing the effect of the corpus luteum of the ovary to die down and signalling the start of a new menstrual cycle. The implants of endometriosis produce their own prostaglandin surge several days after that of the womb lining. This may be one of the main causes of very early miscarriage. If a woman is a few days pregnant then the endometriosis implants producing prostaglandin F would incorrectly signal the ovary to start a new menstrual cycle, causing the womb lining with the implanted egg to be expelled and the consequence is an early miscarriage. Prostaglandins also play an important role in the contractions of womb and fallopian tubes. During the normal menstrual cycle, the gentle contraction of the womb and fallopian tube

aids the movement of egg and sperm to the outer third of the fallopian tube where fertilisation occurs. High concentrations of endometriosis implants may prevent fertilisation. An excess of PGF2 and PGE2 could cause contractions that are too strong and expel the egg too quickly. 2.5 PROSTAGLANDINS AND PARTURITION

Prostaglandins, particularly PGF2, are known to be potent stimulators of uterine contractility and induce cyclic contractions of the gravid uterus. Elevated prostaglandin concentrations are associated with the onset of spontaneous labour in humans. Furthermore, the period of time preceding the onset of contractions is characterized by plasma PGF2 levels that are equivalent to those of non-pregnant women. Immunization against PGF2 also delays the onset of parturition (Csapo, 1977). Prostaglandins are now used to induce early labor and abortion; indeed, prostaglandin is the drug of choice for accomplishing mid-trimester abortions (Goldberg and Ramwell, 1975).

CHAPTER THREE 3.0 CONCLUSION

The many actions of the prostaglandins in reproductive physiology are truly remarkable, as is our rapidly expanding knowledge of these effects. Knowledge remains far from complete. However, much more research is needed to fully elucidate the role of prostaglandins in many physiologic processes, particularly in areas such as luteolysis, where the hope is that these biologically active lipids may provide a method for regulating menstruation and fertility. Further developments in prostaglandin research are likely to include the clinical application of more selective inhibitors, antagonists, and long-acting superpotent agonist analogues of prostaglandins.

REFRENCES

Armstrong D T, Grinwich D L, Moon Y S et al (1974): Inhibition of ovulation in rabbits by intrafollicular injection of indomethacin and prostaglandin F antiserum. Life Sci 14: 129.

Beers W H, Strickland S, Reich E (1975): Ovarian plasminogen activator: Relationships to ovulation and hormone regulation. Cell 6: 387.

Behrman H R (1979): Prostaglandins in hypothalamo-pituitary and ovarian function. Ann Rev Physiol 41: 685

Books.google.com, Self-Assessment in Biochemistry. Csapo A I (1977): The fetus and birth. Ciba Found Symp 47: 159. Goldberg V J, Ramwell P W (1975): Role of prostaglandins in reproduction. Physiol Rev 55: 325.

Marsh J M, Yang N S T, LeMaire W J (1974): Prostaglandin synthesis in rabbit graafian follicles in vitro: Effect of luteinizing hormone and cyclic-AMP. Prostaglandins 7: 269.

O'Grady J P, Caldwell B V, Auletta E J et al (1972): The effects of an inhibitor of prostaglandin synthesis (indomethacin) on ovulation, pregnancy and pseudopregnancy in the rabbit. Prostaglandins 1: 97.

Orczyk G, Behrman H R (1972): Ovulation blockade by aspirin or indomethacin: In vivo evidence for a role of prostaglandins in gonadotropin secretion. Prostaglandins 1: 3.

Robinson J, Vane J R (1974): Prostaglandin Synthesis Inhibitors: Their Effects on Physiological Function and Pathological States, pp 271287.

Swanston I A, McNatty K P, Baird D T (1977): Concentration of prostaglandin F2 and steroids in the human corpus luteum. J Endocrinol 73: 115.

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Zreik, T, Behrman, H (2008), The Prostaglandins: Basic Chemistry and Action.