In 1930 two gynecologists, Kurzrok and Lieb1 working in New York, examined the effects of human seminal fluid on strips of uterine muscle in organ baths. Uteri from fertile women with a history of sterility contracted. In addition, however, the same strip could relax in response to a sample from a different donor. In essence, these findings reflected what is a continuing trend in the prostaglandin (PG) literature for both interesting yet contradictory results. Shortly afterwards von Euler2 proposed the name prostaglandin for one of the active principles in extracts from prostate glands. It was not until 1966, however, that the absolute chemical structure of prostaglandins was defined by Nugteren, van Dorp, Bergstrom, Hamberg and Samuelsson3. The initial steps in the elucidation of the fatty acid precursors for prostaglandin biosynthesis came in 1964 when the conversion of arachidonic acid (a C20 fatty acid precursor) into PGE2 by homogenates of sheep vesicular gland was reported.4,5 The main sources of these precursors are glycerophospholipids from which the fatty acids are released primarily by the actions of phospholipases A2 and
C. Thromboxane A2 and prostacyclin are two newly discovered6,7 prostanoids (prostaglandinlike; usually referring to prostaglandins and thromboxanes) with potent, generally opposing cardiovascular actions. The widely used aspirin-like drugs (e.g. indomethacin, naproxen, mefenamic acid, ibuprofen) all act by of inhibiting prostaglandin synthesis8. In our laboratories, we have demonstrated that human plasma and serum contain endogenous inhibitors of prostaglandin synthase (EIPS) and arachidonate-induced platelet aggregation (EIPA) 9.
Prostaglandins have many and varied properties which make them of interest; three in particular wifi be described. Firstly, they have potent cardiovascular actions with PGE2 generally a vasodilator and PGF2 a a vasoconstrictor.10 Prostacyclin and thromboxane A2 also have, respectively, potent vasodilator and vasoconstrictor properties. Secondly, PGE2 may relax and PGF2a contract smooth muscle although both contract uterine smooth muscle and hence their use for the induction of abortion11,12 and term labor13,14. Prostacyclin is thought either to be without effect on uterine contractility or to be inhibitory of contractility whereas thromboxane A2 may induce uterine contractions15,16 Thirdly, pro stacyclin is a powerful inhibitor of platelet aggregation7 whilst thromboxane A2 is potently proaggregatory6.
Prostaglandins and Mensfruation
Our understanding of the process of menstruation remains limited; much of what is known has been deduced from the classical studies of Markee. in the 1930’s17,18 In these studies Markee transpiated pieces of endometrium to the anterior chamber of the eye of the rhesus monkey (Macca Mulatta) and observed rhythmic vascular changes within the explants throughout the menstrual cycle. Each period of menstrual bleeding was preceded by the following events; a period of endometrial regression resulting in further coiling of the endometrial spiral arterioles andeventually vascular stasis, followed by a period of marked vasoconstriction lasting from 4-24 hours preceding actual haemorrhage. Based on his observation, Markee suggested that a substance or substances produced by the regressing endo. metrium was responsible for this constriction of the spiral arterioles.
It is interesting that other investigators subsequently evaluated the nature of active substances in menstrual fluid, especially one known as menotoxin or menstrual toxin19. As little as 0.02 ml of menstrual discharge could consistently be lethal when administered to immature male rats. The greatest concentration of menstrual toxin was in washed endometrial debris, the equivalent of only 0.005 ml being lethal. The nature of the toxin has still not been clearly established.
In 1957 Pickles20, reported the presence of a smooth muscle stimulant in human menstrual fluid. The major components of the stimulant were identified subsequently as PGE2 and PGF2a21,22
Concentrations of PGE2a and PGF2a in endometrium taken at different stages of the menstrual cycle have been determined by several methods (Table I).
Greater amounts of prostaglandins are found in endometrium taken during the luteal phase of the cycle when compared with amounts in endometrium from the proliferative phase of the cycle. A significant shift in the PGF to PGE ratio, favouring PGF, has often been reported. Endometria obtained during menstruation have been found to contain even greater amounts of prostaglandins as reported by Downie et al (1974)24 These findings are consistent with the enhanced local vasoconstrictive activity thought to precede menstruation. The changes in endometrial prostaglandin content with the phase of the menstrual cycle are not due to alterations in prostaglandin catabolism since the activity of NAD+.dependent 15 -hydroxy-prostaglandin dehydrogenasein endometrium is increased during the luteal phase of the cycle30.
Analysis of measurements of prostaglandin concentrations in peripheral plasma during the menstrual cycle have generally not revealed any significant trends during the cycle31,33 although in one study34, a pre-ovulatory and a premenstrual increase in circulating levels of 13 ,14-dthydro-l 5-keto-PGF2 a (PGFM) (metabolite of prostagland in-F) was reported. Administration of prostaglandins to nonpregnant women wifi induce uterine contractions35 this effect occurs in early pregnancy and is the basis for the use of prostaglandins for menstrual regulation or post-conceptional therapy36,37 Interestingly although administration of PGF2 a is inhibitory of uterine cervical contractility38,39 The latter observations taken in conjunction with the recent observation of striking amounts of prostaglandins in cervical mucus40 may be suggestive of a role for prostaglandins in sperm migration. Presently there is no firm evidence that naturally occuring prostglandins (or analogues thereof) are luteolytic when administered to women.
Prostaglandins and Dysmenorrhoea
Derived from the Greek, meaning “difficult monthly flow” the word dysmenorrhoea has come to mean painful menstruation associated with lower abdominal pain. Many women who suffer from this disorder also suffer from a complex of symptoms that may include headache, weakness, depression, dizziness, paresthesias, nausea, vomiting and abdominal bloating. The symptoms usually appear just before, or at the onset of menstrual flow and persist at their worst during the first day or two of menstruation. In some women, lower abdominal pain can begin several days before menstruation starts and can continue throughout the period of menstruation.
Dysmenorrhoea is classified as primary if it occurs in the absence of pelvic disease. Patients complaining of primary dysmenorrhoea are usually young, nulliparous and have had symptoms since shortly after menarche. Dysmenorrhoea is classified as secondary if it is related to some form of pelvic pathology such as endometriosis, fibroids and pelvic inflammatory disease or to the presence of an intrauterine contraceptive device. Further classification of dysmenorrhoea into spasmoidic (usually primary) or congestive (often secondary) may not be useful, particularly since the elements of congestive dysmenorrhoea e.g. weight gain, abdominal bloating and breat tenderness, are consistent with the premenstrual syndrome or premenstrual tension. Moreover the actual period of menstruation is usually painfree in congestive dysmenorrhoea and hence is difficult to associate with painful menstruation.
Although accurate assessments of the incidence of dysmenorrhoea are not available, several recent studies from the USA, Great Britain and Sweden have provided useful information and calculations41-45 Approximately 50-60% of women of reproductive age experience painful periods. As many as 30% of such women suffer severe pain that can be incapacitating43-44
Endometria from dysmenorrheic women contain greater amounts of prostaglandins than endometria from women without dysmenorrhoea45,46,47 Moreover concentrations PGFM in peripheral plasma taken during menstruation are significantly higher in women with dysmenorrhoea than in eumenorrheic women47 It has been suggested that the increased production of prostaglandins within the uterus could lead to greater uterine activity (and pain) and that sufficient prostaglandins may be secreted into the systemic circulation to cause some of the other symptoms of dysmenorrhoea42. An alternative explanation for the wide-spread symptoms of dysmenorrhoea could be the generation of a noxious substance that reaches the systemic circulation during the period of menstruation. Such a factor has recently been described48. Treatment of dysmenorrhoea with non-steroidal anti-inflammatory drugs (prostaglandin synthase inhibitors, PGSI) does indeed reduce parameters of uterine pressure and work49,50 The first reported trial of a PGSI for the treatment of primary dysmenorrhoea was by Schwartz and colleagues51. Flufenamic acid (125 mg tid or qid) afforded symptomatic relief in all 16 patients in the study during 31 treatment cycles. Since this publication the results of many more controlled, trials of different PGSI for the treatment of dysmenorrhoea have been published52. It should be noted that fenamates could hold an advantage over other PGSI for the treatment of dysmenorrhoea since they may antagonize the actions of prostaglandins, in addition to being inhibitory of prostaglandin biosynthesis53 Overall, approximately 70-80% of women complaining of primary dysmenorrhoea obtain significant relief by ingesting various PGSI (e.g. Table-II).
A significant advantage of this form of treatment is that drug administration can be limited to a few days per month and by restricting use to the period of menstruation fears of effects on an unknown pregnancy can be alleviated.
Endogenous Inhibitor of Prostaglandin Synthase in Dysmenorrhea We have recently demonstrated the presence of endogenous inhibitors of prostaglandin synthase (EIPS) and arachidonate-induced plate aggregation (EIPA) in human blood plasma and serum9.
EIPS activity as measured by the effect of plasma on the net conversion of arachidonic acid to prostanoids has been determined in plasma of women with dysmenorrhea54.
The results given in Table III show no significant differences in EIPS activity of plasma obtained from women who experience dysmenorrhea when compared to those who did not experience it.
Values are the mean (± S.E.) decrease in PGE, production, expressed as a percent of controls. BSV; Bull Seminal Vesicle (ReP 54).
It is possible, however, that because of the potency of EIPS activity in human plasma, the methodology used in the previous study54 was not sufficiently sensitive to detect othei plasma factors in dysmenorrhea which may modulate normal plasma EIPS activity. Alternatively, autocoids, such as vasoactive amines, kinins and opioids, may act in concert with prostaglandins to cause the symptoms that are associated with dysmenorrhea.
Prostaglandins and Menorrhagia
Iron deficiency anaemia may be indicative of heavy blood loss at menstruation and is more common in women whose loss is more than 80 ml per menses55. Thus the most widely used definition of menorrhagia is that of a menstrual blood loss of 80 ml or greater per menses. A woman’s menstrual blood loss usually varies by 20-40% between menses although greater variations may occur in women with menorrhagia56There is a much larger variation in menstrual blood loss between individuals. Intriguingly, it has been found that there is a significant correlation between menstrual blood loss in monozygotic twins which cannot be demonstrated for dizygotic twins56
It is unfortunate that often the main criteria for diagnosing menorrhagia is the patients statement that the has heavy periods. It has been shown that women may not make reliable judgements of the volume of their menstrual blood loss. In one study 40% of women with menstrual blood loss exceeding 80 ml considered their periods to only moderately heavy or scanty whilst 14% of women with a measured loss of less than 20m1 judged their periods to be heavy55. In a recent stud57 it was shown that there was no significant relationship between menstrual blood loss and the patients’ subjective assessment of that loss, the duration of menstruation, uterine weight or endometrial surface area. It has been demonstrated that women with menorrhagia have periods of menstruation that are no longer than women without menorrhagia58.
Excessive bleeding from the uterine cavity may be preceded by ovulatory or anovulatory menstrual cycles. In the majority of women whose menstrual loss has been assessed objectively, no significant differences from normal can be shown in the pattern of pituitary or ovarian hormone secretion59. In a recent study60, the endogenous concentratiQns of prostaglandins F2 a (PGF2 a) and E (PGE) were measured during the luteal phase of the menstrual cycle in the endometrium from 14 women with unexplained menorrhagia measured menstrual blood loss in excess of (5Oml) and 15 women with normal menses (blood loss 50 ml or less). Although there was no significant differences in the PGF2 aPGE ratio between the two groups, this ratio was significantly lower in the endometrium from eight of the women whose blood loss exceeded 90m1 (p< 0.05). There was a significant inverse correlation between the PGF2 a ratio and blood loss (r = 0.36, p < 0.025). The synthetic capacity of the endometrium was assessed by incubation of the tissue whh C,4 arachidonic acid. Endometria from nine women with unexplained menorrhagia synthesized more PGE2 than PGF2 a, whereas the converse was true with 11 control endometria. Consequently the PGF2 a/PGE2 ratio was significantly reduced in the former group.
These results are suggestive that excessive blood loss may be associated with a shift in the endometrial conversion of prostaglandin endoperoxide from PGF2 to PGE2.
The same group of investigators61 subsequently have found that endometria from women with excessive menstrual blood loss are more effective than endometria from women with normal menstrual blood loss at enhancing the production of 6-keto-prostaglandin F, a (the degradation product of prostacycin) by a control preparation of myometrium. These workers suggested that an enhanced ability of the uterus to generate prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, could influence the degree and duration of menstrual bleeding.
In 1976, Anderson and colleagues62 published the results of a trial of PGSI (mefenamic acid and flufenamic acid) for the treatment of menorrhagia due to dysfunctional uterine bleeding. In every patient mean blood loss was reduced during treatment; the pre-treatment value was (mean * SEM) 119 ± 10 ml (18 cycles in six patients) and the treatment value was 60 ± 7 ml (17 cycles in six patients). The presence of an intrauterine contraceptive device is associated with increased menstrual blood loss and there is evidence that the PGE content of endometrium is also increased under these conditions63. Mefenamic acid has been used successfully to reduce menstrual blood-loss in women using intrauterine contraceptive devices64. This treatment however does not alter total duration of bleeding or noncollectable spotting. Expressed as a percentage of the mean pretreatment volume, the reduction in loss was not significantly different for those women who were light losers (less than 80 ml) compared with heavy losers (80 ml or more), but it was greater in volume terms among the latter. The successful use of PGSI in the treatment of menorrhagia lends credence to the view that the mechanism of this disorder involves altered prostaglandin production.
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