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PROGESTOGENS USE IN THE MENOPAUSE

The use of progestins in the menopause is being re-evaluated in the light of recent research findings.

The past two years have seen increasing attention being focused on the progesto- gens. The findings, as regards breast cancer, from the two arms of the Women’s Health Initiative (WHI)1,2 study supported the findings of previous observational studies that the addition of a progestin increased the risk of breast cancer above that of oestrogen alone. The lack of protection against ischaemic heart disease afforded by menopausal hormone therapy as shown in the WHI and HERS3,4 studies also led to questions being asked about the influence of the progestin used. A re-evaluation of progestogen use in the menopause is occurring.

CLASSIFICATION OF THE

The term progestogen applies to both natural and the synthetic progestins. Natural progesterone, even in the micronised form, shows a wide variation in absorption in the individual patient.

MIKE DAVEY The synthetic progestins are far more rapidly absorbed, reaching a peak serum MB BCh, FCOG (SA) level in 2 - 5 hours. The progestins used in menopausal hormone therapy prepa- rations were chosen primarily for their ability to protect the endometrium. The Gynaecologist in private practice one effect they have in common is their ability to turn an oestrogen-primed Westville Hospital endometrium from a proliferative into a secretory pattern. They vary widely in Durban their other effects, including oestrogenicity, androgenity, glucocorticoid and min- eralocorticoid effects.

Mike Davey practises mainly in the fields of Table I. Progestogens available in South Africa menopause and osteoporosis. He is a founder Parent compound Progestogen member and the present Vice-President of the South African Menopause Society. He quali- Progesterone Micronised progesterone fied at the University of the Witwatersrand, and has been in private practice for the past Progesterone derivative 18 years. 17α-OH-progesterone derivatives acetate (Pregnanes C21) 19-nor-progesterone derivatives (19-nor-pregnanes C20) 19-nor- derivatives Estranes (C18) Gonanes (C17) derivatives Drosperinone

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The term progestogen THE NEED FOR sia is low with this type of therapy, applies to both natural PROGESTOGEN USE IN there is still an increased risk com- progesterone and the syn- MENOPAUSAL HORMONE pared with opposed therapy, even THERAPY after only 2 years.6 thetic progestins. Natural progesterone, even in the The findings of increased risk of breast Other methods of administering micronised form, shows a cancer with the use of a progestin progestogen have been considered. wide variation in absorp- have prompted a review of the need Long-term sequential therapy results in for their use. The sole reason for using a small increased risk of endometrial tion in the individual a progestin is endometrial protection. patient. cancer compared with continuous com- The authors of the Million Women bined therapy.8 The same problem 5 Study, a large observational study would therefore apply to long-cycle that confirmed the increased risk of The findings of increased therapy. breast cancer with the use of progesto- risk of breast cancer with gen combined with oestrogen, suggest- An alternative that has been proposed the use of a progestin have ed that there may be no place for the is the use of intrauterine progestin in prompted a review of the use of a progestogen because the the form of the progestin-containing need for their use. increased risk of endometrial cancer intrauterine contraceptive device was outweighed by the comparatively (Mirena). This is available in South decreased risk of breast cancer in Africa in a 20 µg form, and a 10 µg Oral oestrogen therapy has unopposed oestrogen users. They cal- form (not yet available in South Africa) a beneficial effect on both culated that 10 years’ use of unop- has been developed especially for use LDL cholesterol and HDL posed oestrogen would produce 5 in menopausal patients. This is an extra breast cancers and 10 extra cholesterol, lowering the attractive option that has been shown endometrial cancers per 1 000 former and raising the lat- to control bleeding and although long- women compared with 19 extra breast term observational studies are not yet ter. cancers and no extra endometrial can- available, it would appear to ade- cers using a combined oestrogen-prog- quately suppress the endometrium. The estin preparation for the same dura- In all likelihood, in the amount of progestin released into the tion. It should however be realised circulation is much lower than with patient at low risk for either that these figures applied only to the oral administration.6 However, there is breast or cardiovascular patients in the 50 – 64-year age still a significant amount of progestin disease, it will make no dif- group and that even after oestrogen is absorbed and there is no evidence at ference which progestogen discontinued, the risk for endometrial this stage that the effect on the breast cancer remains increased for the next is used and the choice will or cardiovascular system would be 10 years.6 The numbers as calculated often be based on patient any different. Further research is need- by the Million Women Study would ed on this promising mode of therapy. tolerance. therefore be an under-estimate. There has even been the suggestion There is also the issue of the abnormal that there should be a move back The progestins are classified accord- bleeding patterns that will inevitably towards hysterectomy to allow unop- ing to their derivation from a particu- develop with unopposed oestrogen posed oestrogen. With the advent of lar parent compound. Table I lists and the increased intervention in the less invasive means of controlling dys- some of the progestogens available form of endometrial biopsies, hys- functional uterine bleeding, there has for use in menopausal patients in teroscopy and dilatation and curettage been a move away from hysterectomy. South Africa. The 19 nor-progesterone that would be required for endometrial The incidence of morbidity associated derivatives are not available in South assessment in patients on unopposed with hysterectomy is high, and there Africa at this stage but are included oestrogen. Very-low-dose oestrogen would appear to be no justification at because of their potential for future replacement has been shown to ade- this stage for a move back towards use due to their high specificity for the quately suppress bone resorption, has this invasive and potentially dangerous 7 , allowing ade- a favourable effect on blood lipids, procedure purely to avoid using quate progestogenic effect at low and will control vasomotor symptoms progestogens in the menopause. doses. in most patients. However, although Patients who have had endometrial the incidence of endometrial hyperpla- ablation still require endometrial pro-

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Table II. Differential effects of progestogens

Progestogen Oestrogenic Androgenic Anti-androgenic Glucocorticoid Anti-mineralocorticoid Progesterone - - +/- + + Didrogesterone - - +/- - +/- Medrogestone - - +/- - - 17a-OH-derivatives Medroxyprogesterone acetate - +/- - + - Cyproterone acetate - - ++ + - 19-nor-progesterone derivatives Promegestone - - - - - Trimegestone - - +/- - +/- 19-nor-testosterone derivatives Norethisterone + + - - - Levonorgestrel - + - - - Norgestimate - + - - - Dienogest +/- - + - - Desogestrel - + - - - Gestodene - + - + + Spirolactone derivatives Drosperinone - - + - +

tection with a progestogen as pockets progestogens. We therefore have to A difference is also seen in the effect of endometrium may remain. rely on indirect evidence in order to on insulin resistance, with androgenic decide if there is potential advantage progestins increasing insulin resistance THE USE OF DIFFERENT in using alternative progestogens. and therefore decreasing glucose toler- PROGESTINS ance.10 Progesterone, dydrogesterone CARDIOVASCULAR SYSTEM and drosperinone have no adverse If we therefore accept that at present effects in this regard. The adverse the balance of evidence is that we The different progestins differ in their effect of decreased glucose tolerance need to use a progestogen, we need effect on intermediate markers of car- on the cardiovascular system is well to look at whether the use of a differ- diovascular risk such as blood lipid established. ent progestogen may have resulted in levels. Oral oestrogen therapy has a a different outcome, as regards breast beneficial effect on both LDL choles- That there is a difference in the direct disease and cardiovascular disease, in terol and HDL cholesterol, lowering the effects of different progestogens on the studies such as WHI and HERS. These former and raising the latter. The vasculature is shown in a study by studies used a combination of conju- more androgenic progestogens, such Thomas,11 who looked at the acute gated equine oestrogen (CEE) and as norethisterone acetate (NETA), MPA vascular actions of progesterone, medroxyprogesterone acetate (MPA). and levonorgestrel, oppose both of MPA, norethisterone, CEE and 17ß The progestins used in current prepa- these effects. This is not seen with the oestradiol on peripheral and cerebral rations were chosen more for their less androgenic progestogens such as blood vessels of rats. Both MPA and ability to suppress oestrogen-induced dydrogesterone, drosperinone and norethisterone caused endothelial thickening of the endometrium rather micronised progesterone. However the damage leading to inflammation and than for other effects and, as stated more androgenic progestogens thrombosis. This was not seen with above, they differ in many aspects, as oppose the potentially adverse progesterone or the oestrogens. seen in Table II.9 increase of triglyceride seen with oral Although we must be careful about oestrogen administration. The increase extrapolating this in vitro finding to the There are no long-term observational in triglyceride is however generally clinical situation, it is clear that there studies or randomised control trials within normal limits and its signifi- are differences in effect that could comparing the effects of these different cance is debatable.9 have significant clinical implications.

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There are also differences as regards non-androgenic progestins have fur- that different progestogens differ in haemostasis. Oral oestrogen decreas- ther potential benefit in that they their effects on both the breast and es antithrombin III (AT III), protein C encourage increased sulphatransferase cardiovascular system and that there and protein S. This increases coagula- activity that results in the conversion of may be advantages in using less tion and may partly explain the oestradiol to the less biologically androgenic progestogens in patients increase in incidence of thrombosis active oestradiol sulphate. at higher risk for breast or cardiovas- seen with oral oestrogen therapy. MPA cular disease if the decision is taken to also significantly decreases AT III activ- Apoptosis is an important and benefi- use menopausal hormone therapy. This ity whereas dydrogesterone has far cial process in the removal of dam- further highlights the need for individu- less effect.12 aged and potentially malignant cells. alisation of therapy in menopausal Franke14 looked at the apoptosis prolif- women. BREAST eration ratio of MCF-7 breast cancer References available on request. cells exposed to progestins alone and In order to understand the potentially in combination with oestradiol. adverse effects of progestogens on the has the highest degree of breast, it is necessary to understand apoptosis followed by the less andro- the effect of oestrogen on the breast in genic progestogens. The more andro- menopausal women.13 Oestrogen genic progestins had an apoptosis results in an increase in proliferation proliferation ratio well on the side of IN A NUTSHELL of breast tissue. Oestradiol is the most proliferation. biologically active oestrogen. Recent publications of prospective Oestrone sulphate is the dominant cir- The previously mentioned effect of the randomised controlled trials have culating oestrogen in menopausal androgenic progestins in increasing called into question the role of women. Oral oestrogen therapy results insulin resistance may also be signifi- progestogen use in menopausal in increased levels of oestrone. There cant as regards the breast as their women. are various enzyme pathways that will effect of increasing both insulin and determine the amount of oestradiol insulin-like growth factor I, which are Progestogens are necessary to pro- that accumulates in the breast tissue potent mitogenic peptides, may play a tect the endometrium from the hyper- and therefore the potential for prolifer- role in breast cancer.15 plastic effect of oestrogen. ative activity and stimulation of tumour growth. Oestrone sulphatase converts CONCLUSIONS Progestogens differ markedly in their oestrone sulphate to oestrone. This is effects on different organ systems. then reduced by 17ß-OH dehy- Recent randomised control trials have drogenase to oestradiol. The signifi- shown that the use of progestogens In the cardiovascular system, the less cance of this is shown by the fact that may impair potentially beneficial androgenic progestogens have sulphatase activity has been shown to effects and enhance adverse effects of potential advantages as regards be far more intense in malignant and oestrogen administration in their effect on lipid profile, direct benign breast tumours than in normal menopausal women. Present evidence vascular effect, insulin resistance breast tissue.14 Non-androgenic however still supports the use of a and haemostasis. progestogens such as progesterone progestogen to protect the endometri- and dydrogesterone inhibit oestrone um in menopausal women. There is no By virtue of their effect on breast tis- sulphatase activity. This benefit is also grade I evidence that the use of any sue enzymes, progestogens may seen with tibolone. These non-andro- other progestogen, different to that increase the concentration of oestra- genic progestogens also appear to used in the currently available diol in breast tissue. Progestins differ favour the oxidative process whereby prospective randomised controlled tri- in this effect. oestradiol is converted to the less bio- als, would have resulted in a different logically active oestrone rather than outcome. In all likelihood, in the Less androgenic progestogens have the reductive process, resulting in patient at low risk for either breast or a favourable effect on the apoptosis increased oestradiol levels. The andro- cardiovascular disease, it will make proliferation ratio in breast tissue. genic 19-nor-testosterone derivatives no difference which progestogen is do not have either of these effects, used and the choice will often be Individualisation of menopausal hor- showing potential benefit for the use based on patient tolerance. However, mone therapy is important, especial- of a non-androgenic progestin. The there is interesting indirect evidence ly in the high-risk patient.

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