Two new types of antiprogestins havebeen shown to reversibly suppress men-struation, and could provide a reliablemethod of menstrual control for women.Scientists at the Oregon Regional PrimateResearch Center (ORPRC; Beaverton, OR,USA) have recently published preclinicaldata1 in rhesus macaques identifying the different doses of antiprogestins(progesterone antagonists; PAs) that canblock menstruation and, depending onthe dose, also block ovulation, in a re-versible manner. The rhesus macaque isa useful model of menstruation becauseit is one of the only animals that regu-larly menstruates, and its hormonal control of menstruation is similar to that in women.

A reliable method of menstrual sup-pression could greatly enhance the qual-ity of life for many women, particularlythose who suffer from excessive bleed-ing (which often requires treatment byhysterectomy) or in stressful occupationssuch as the military. Although the com-bined oestrogen and progesterone con-traceptive pill can serve this purpose, it is not suitable for all women because ofhealth risks such as increased blood-clotting and breast cancer, and is oftenassociated with unfavourable side-effects.

Normal menstruationThe term menstruation describes thebleeding and sloughing of the uterineendometrium, which consists of two distinct layers: the basal layer (stratumbasale) and the functional layer (stratumfunctionale). The basal layer undergoeslittle cyclic change, whereas the func-tional layer arises from the basal layerduring each menstrual cycle in response

to hormonal stimuli, and is shed in theabsence of a fertilized egg (menstruation).

The development and subsequentshedding of the endometrium occurs inthree distinct phases, during which thelevels of several reproductive hormonesvary. First, during the proliferative phase,the cells of the functional layer grow in response to high oestrogen levels.Second, progesterone levels peak andstimulate the secretory phase duringwhich egg implantation would occur;and third, in the menstrual phase, theabsence of human chorioid gonado-trophin (hCG) secreted by an embryocauses progesterone levels to drop. Thehighly specialized vasculature of thefunctional layer, known as spiral arteries,then constricts in response to reducedprogesterone levels, causing hypoxia, ischaemia and subsequent tissue break-down, which results in menstruation.

Antiprogestin actionPAs block the action of progesterone,which is the predominant hormone inthe second half of the menstrual cyclethat induces the development of thefunctional layer of the endometrium. If,therefore, PAs are administered beforethe functional layer fully develops, thenno menstruation will occur. Similarly, ifPAs are administered at a dose that is sufficient to block ovulation, then theovary will not produce the progesterone required to build up the endometrium.

Brenner and colleagues at the ORPRChave carried out three different studiesin macaque monkeys1. First, using two recently identified antiprogestins,ZK137316 and ZK230211, which aretype II and type III antiprogestins,

respectively, they established the doserange that would block progesterone action directly on the endometrium inartificially cycled, spayed macaques.Second, they studied the histological ef-fects of ZK230211 on the endometrium;and third, they determined whether re-versible menstruation could be achievedin normal, cycling rhesus monkeys afterchronic administration of both ZK137316and ZK230211 at doses that suppressendometrium development.

Dose studiesTwo dose-finding studies were carriedout in ovariectomized rhesus macaquesduring hormonally regulated, artificialmenstrual cycles: (1) to determine thedose of PA given chronically throughoutone menstrual cycle that would blockmenstruation on progesterone with-drawal, and (2) to determine the dosethat would induce menstruation whengiven acutely at the end of a menstrualcycle.

Brenner and colleagues found thatZK230211 was three–fivefold more po-tent than ZK137316 at inducing bleed-ing in the menstruation induction study. Histological observations, such asreduced mitotic and elevated apoptotic indices, endometrial shrinkage (Fig. 1),stromal compaction, glandular atrophyand hyalinizating degeneration of thespiral artery wall showed that ZK230211was also approximately threefold morepotent than ZK137316 at suppressingthe proliferation of the functional layerof the endometrium in oestradiol andprogesterone-primed animals.

In another experiment, immunocyto-chemistry was used to measure the

DDT Vol. 6, No. 19 October 2001 updatenews

1359-6446/01/$ – see front matter ©2001 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(01)01982-1 975

New option for reversible suppressionof menstruationJoanna Owens, joanna.owens@drugdiscoverytoday.com

levels of progesterone and oestrogen receptors (PR and ERα, respectively).Administration of the PAs had blockedthe suppressive effect of progesteroneon both the PR and ERα. Furthermore,the anti-progesterone activity ofZK230211 was sufficient to block theprogesterone-dependent growth of thebasal endometrial layer, which, in rhesusmacaques, contributes to overall endo-metrial growth during the second half of the cycle. The suppressive effects ofprogesterone on oviductal growth anddifferentiation were also blocked by PA treatment. These are the first data that demonstrate low-dose modulationof the endometrium and oviduct byZK230211 in spayed, cycling macaques.

Menstrual suppressionFrom the previous dose-finding studies,Brenner and colleagues were able tochoose doses at which to study the ability of PAs to suppress menstruation in ovarian-intact animals undergoing normal menstrual cycles. Two studies (40-day and 100-day) were conductedwith ZK137316 and one study (60-day)

with ZK230211, to mimic cases wherewomen might want to block either oneor several menstrual periods.

Treatment with ZK137316 at either0.05 mg kg−1 or 0.10 mg kg−1 blockedmenstruation in all animals and sup-pressed ovulation in ~50% of the animals. In animals that ovulated,ZK137316 antagonized progesterone-dependent endometrial development, asshown by the absence of menstrualbleeding. By contrast, ZK230211 wasfound to be far more potent thanZK137316 because a dose of 0.016 mgkg−1 completely suppressed both ovu-lation and menstruation. Interestingly,Brenner and colleagues noted a signifi-cant suppression of luteinizing hormone(LH), which suggests that ZK230211 isexerting its anti-ovulatory actions via the hypothalamic–pituitary axis2.

The difference in action and potencybetween the two PAs suggests thatZK230211 is a pure PA, that is, it has noagonist activity for the progesterone receptor. By contrast, the anti-ovulatoryand anti-endometrial effects of ZK137316were dissociated, and other data3

suggest that this compound might act asa partial agonist. There is a potential,therefore, for two separate therapeuticapproaches with these compounds de-pending on whether blockade of ovu-lation is required.

Brenner described important aspectsof this type of therapy as follows: first,the ovulatory blockade induced by PAswas accompanied by normal levels of cir-culating oestradiol, which would favournormal oestradiol action in the skeletaland vascular systems; for example, hotflushes would not occur. Second, PAtreatment should, through its endome-trial antiproliferative effect, prevent therisk of endometrial cancer resulting fromunopposed oestrogen action.

David Baird from the Department ofReproductive Biology at the University ofEdinburgh (Edinburgh, UK) thinks thisresearch is encouraging. His researchgroup have used very low doses ofmifepristine (RU486, known as the abor-tion pill) to induce amenorrhoea in 90% of the women studied. He said,‘[Menstrual suppression] is an area thatwe are particularly interested in, in ourcapacity of trying to develop new meth-ods of contraception, and a number ofus have felt for a long time that there’sroom for a method of contraceptionwhich induced amenorrhoea. We’ve justcompleted quite a big international sur-vey including women in Edinburgh, two centres in Africa, and in Asia, to see howacceptable a method of induced amen-orrhoea would be and whether womenwould welcome it. The data is still underanalysis, but the bottom line is that themajority of women in each of these centres say that, yes, they would like induced amenorrhoea. For example, inEdinburgh [this majority] was ~65%.’ Hecontinued, ‘So, I think this is a very encouraging development, the use ofcompounds that induce a degree of at-rophy of the endometrium…the healthbenefits are really quite substantial, [aswell as] the social convenience of notmenstruating’.

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Figure 1. Photomicrographs of haematoxylin-stained sections of full-thickness endometrium.(a–d) show the decreasing thickness of the endometrium with increasing doses ofZK230211. The black line indicates the endometrial–myometrial border. The arrow in (d)points to a dilated vein. Abbreviations: E2, oestradiol; P, progesterone; ZK, ZK230211;Endo, endometrium; Myo, myometrium. Reproduced, with permission, from Ref. 1.

End

omet

rium

– fu

ll th

ickn

ess

(a) (b) (c) (d)

E2 + P E2 + P+ 0.005 mg ZK

E2 + P+ 0.016 mg ZK

E2 + P+ 0.032 mg ZK

ZK230211

1 mm

Are antiprogestins safe?After treatment, the menstrual cycles ofthe animals were observed to be normal,demonstrating the lack of any residualeffect and the complete reversibility ofmenstrual suppression. Research is nowneeded in women to establish whetherPA-mediated menstrual suppression issafe, and whether it might affect fertilityin the long term. However, Brennanpointed out that women currently useintra-uterine devices (IUDs) that sup-press menstruation for years without ill effect, and rhesus macaques given antiprogestin in a one-year unpublishedORPRC study showed no ill effect aftertreatment, and a complete return to normal fertility. He adds that, ‘When we

conducted these studies, we had inmind women in the military, the spaceprogram or in other stressful jobs wherea short-term suppression of menseswould be useful. Not all women can usethe pill to accomplish this. We also feltthat suppression of excessive bleedingwould be an aid to the clinical manage-ment of menorrhagia and perhaps re-duce the need for hysterectomies, mostof which are done to reduce excessivebleeding.’

Brenner is uncertain as to when clini-cal trials of antiprogestins could begin,but predicts that it might be within a few years depending on the interests of patient populations, clinicians and the pharmaceutical industry. He and his

colleagues are now working on how antiprogestins induce their specific anti-proliferative effects in the endometrium.

References1 Slayden, O.D. et al. (2001) Reversible

suppression of menstruation withprogesterone antagonists in rhesusmacaques. Hum. Reprod. 16, 1562–1574

2 Zelinski-Wooton, M.B. et al. (1998) Chronictreatment of female rhesus monkeys withlow doses of the antiprogestin ZK136316:establishment of a regimen that permitsnormal menstrual cyclicity. Hum. Reprod.13, 259–267

3 Chwalisz, K. et al. (2000) A comparison of theendometrial effects of a mesoprogestin(J1042) with the antiprogestins ZK137316and ZK230211 in cynomolgus monkeys. InSociety for Gynecologic Investigation Programand Abstracts, 47th Annual Meeting, 22–25March 2000, Chicago, IL, USA, Abstract 221A

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In the 15th October 2001 issue of Drug Discovery Today…

Update news and views● Steven Holtzman on partnering● Personalia to celebrate Craig Venter’s 55th anniversary● Conclusions on process R&D, and DNA microarrays and integrative virogenomics are

discussed in the Forum● Book review of Project Management For Successful Product Innovation● Up-to-date News, News in brief and People

Reviews Cholesterol modulation as an emerging strategy for the treatment of Alzheimer’sdiseaseby Todd E. Golde and Christopher B. Eckman

Insulin therapies: past, present and futureby Omathanu Pillai and Ramesh Panchagnula

Human disease characterization: real-time quantitative PCR analysis of gene expressionby James V. Snider, Mark A. Wechser and Izidore S. Lossos

Monitor Molecules, novel antitumour molecules, combinatorial chemistry and profile