Roy Homburg, MD

 “My name is Roy Homburg.  I am the Professor of Reproductive Medicine at the Free University in Amsterdam.  I have with me today Dr. Adam Balen, who is a Consultant Gynaecologist and  Obstetrician at the Leeds General Infirmary, which is part of Leeds University. 
 
 We are going to talk about a very hot issue and that is finding a consensus for  the diagnosis of the polycystic ovaries. This has come up very much lately  because there was a consensus meeting in Rotterdam where the idea was to unify  the criteria that we have so that we will all be talking about the same thing,  which is very important both for clinical and particularly for scientific  purposes. Adam, I am going to ask you first of all, what were your impressions  from the meeting? Did we succeed in the aim?”
 
 

 “I think it was an extremely  interesting meeting. There was some excellent interaction and great discussion.  There’s no doubt that historically there have been some differences, most  noticeably I suppose, the differences that have been expressed as the  transatlantic divide and the inclusion of the ultrasound criteria for polycystic  ovaries. 
 
 What I thought was most interesting was actually hearing about the practical  approach to the management of the woman and the likelihood that it may just be  simply the fact that in the United States many women go and see a reproductive  physician or an endocrinologist, whereas in Europe and Australia it’s often the  gynaecologist. There are those of us of course as gynaecologists and infertility  specialists who have developed an interest in the syndrome and embrace the  endocrinological aspects as well.”
 
 

 “I think you are quite  right in emphasising that Polycystic Ovary Syndrome has gone way beyond being  just a gynaecological curiosity. It’s now really part of a multi-system  endocrinopathy. 
 
 Now I suppose that one of the basic summaries and really the headlines of the  meeting were that it was decided that if we have two out of three criteria it  would be good for the diagnosis of the PCOS. An irregularity of the period,  either oligoamenorrhoea, which means really chronic anovulation, the appearance  of polycystic ovaries, and hyperandrogenism, which could be either clinical or  endocrinal, that is to say laboratory evidence, and we decided that two out of  three would make the diagnosis. Do you think that there’s going to be a chance  of this being accepted worldwide which would, of course, be a great advance for  us?”
 
 

 “I very much hope so. I mean  there are naturally going to be some people who may feel a little bit  uncomfortable. I think that the strength of having this syndrome being  recognised as two out of the three criteria is not so proscriptive. Particularly  we didn’t get too bogged down on looking at levels of testosterone or  classification of hirsuitism other than recognising that signs of  hyperandrogenism are subjective and depends both on the symptoms of the  individual woman, the assessment by the physician and ethnic and racial  differences as well, which we all recognise. 
 
 I feel that the syndrome as we have presented it is all encompassing and that’s  the strength. When it comes to specific research studies, as long as the  researcher is clearly identifying and quantifying the group of patients they are  dealing with, then you can make the right conclusions. I think that was one of  the other pleas from the meeting was that people when writing about their  patient groups simply provide an absolutely clear definition of what they mean.”
 
 

 “Yes, I agree with you.  Now, I think that if this consensus is accepted, and I really believe it will  be, it’s going to be presented, is being presented by Adam here initially. It  will be presented at the ASRM, the American meeting and it is going to be  published in both Human Reproduction and Fertility and Sterility, so I think we  have a good chance of it being accepted. This is a golden opportunity of course  certainly to get the scientific angle right, especially with things when we are  looking for the phenotype to match the genotype. If we’re looking for the genes,  that overall group of genes, that almost certainly cause PCOS then we must be  all talking about the same thing. I think this is going to be a great advance.”
 
 

 “One of the points that came  out in the discussion we were having this afternoon was the whole issue of  whether we will be detecting more women with polycystic ovaries now that we’ve  included ultrasound in the diagnosis. I personally feel that’s probably not  going to be the case because certainly in our practice we use ultrasound but I  think the implications for the patient who may have an ultrasound scan for  whatever reason and is then found to have polycystic ovaries causes some  disquiet because the question then is posed what should you say to that  individual?”
 
 

 “Yes but I think we should  distinguish, and it might help to clarify this, that I think we both believe  that there is a condition where you may have polycystic ovaries but not the  syndrome. In that case it might be a question of what do you say to the patient?  My own inclination, if she has no clinical signs or symptoms, you probably not  need say anything, unless maybe she’s obese and advise her to not put on too  much weight.”
 
 

 “I disagree slightly with  you there because I would, and I’m sure you would, if you see something on the  scan you’d actually tell them what you’ve seen, but there may be an opportunity  to suggest that it is appropriate to watch lifestyle matters such as diet and  exercise even in the slim women in whom you see polycystic ovaries because we  all know that with a gain in weight the syndrome will be expressed. 
 
 Of course, we still don’t know enough about the evolution of the condition, but  there was an interesting study presented this morning from Rome on the growth  hormone secretion in response to food, and the effect on opioides and the  suggestion, without going into all the details because it’s quite a complex  study, they did find differences in opioid tone, in the slim women, posing the  possibility that there may be already some inherent difference in satiety and  appetite, how you enjoy your food, that may predispose the slim women with  polycystic ovaries to be more likely to gain weight. That’s still conjecture, I  appreciate that.”
 
 

 “Yes, it also works the  opposite way around. It seems to me, and I think there’s good proof of this that  it’s much more difficult to get PCOS women to slim. They have great difficulty  cutting down their intake. I think it’s probably worth mentioning the work of  Rob Norman in Adelaide, who has proved very clearly that changing lifestyle can  greatly affect the fertility potential and I think everybody should take notice  of this sort of advice.”
 
 

 “And furthermore that it’s  the lifestyle changes of exercise and diet that have been shown to be far  superior to drugs such as metformin, which whilst it may well have a valuable  role, and of course the consensus meeting didn’t deal with treatment, there is  this sort of world wide view really isn’t there, that everybody is prescribed  metformin.”
 
 

 “Yes, which is pretty  typical of what goes on without any really very good evidence-based medicine  this is what’s happened. I want to go back to the point we mentioned before  about widening the diagnostic criteria. The question was asked is that going to  increase expenses, is that going to increase the examinations we do? My personal  point of view is it’s much better to catch these women who eventually, if not  now, will need treatment. So I’m quite pleased that we have slightly broadened  the criteria for inclusion.”
 
 

 “It also presents the  opportunity to study the cohort long-term.”
 
 

 “Exactly. Any thoughts of  what’s going to be? Is it going to be okay? Are we going to manage to get this  through?”
 
 

 “I’m sure it will be  through. I think it was fairly warmly received today.”
 
 

“It is quite, well I  wouldn’t say outstanding, but certainly the PCOS parts of this meeting have been  packed. Every session has been completely packed.”
 
 

 “Yes, they always are and I  think this is a very good indication of how important it was to get a consensus,  to get absolute guidelines of what we mean and if we do this to packed houses  every time then I think we’ll do it in the end.”
 
 

 “Anything else you want to  add?” 
 
 

 “I could talk about the  ultrasound and I don’t think you want me to go into the details, but we have  defined what we mean by a polycystic ovary as detected by ultrasound now. And  because ultrasound is part of the criteria it is something that can be  quantified and there have been many correlations performed between the various  ultrasound measurements and both signs, symptoms and endocrine disturbances in  PCOS. It is quite difficult to synthesise all the literature but in summary we  feel that a polycystic ovary is one that has at least 12 follicles between 2 and  9 mm in diameter and/or an ovarian volume of greater than 10 ml. There are  various other criteria which I don’t think time allows me to go through but  that’s the nuts and bolts.”
 
 

 “Yes, I agree and certainly  by narrowing these criteria down I think people will feel very much more  comfortable. So we’re going to have definite criteria for ultrasound and for the  actual diagnosis itself. Not only that, I think we’ve made it quite plain that  we don’t need any sophisticated endocrine examinations. Maybe a simple  testosterone would do: probably confirm the diagnosis if we exclude other causes  of hyperandrogenemia, and it also would make the endocrine work up very much  simpler.”
 
 

 “Yes, this is all about  taking a pragmatic approach to the management of this common condition.”
 
 

 “Yes, do you think it’s  going to change the treatment in any way? Or isit just going to broaden the  indications?”
 
 

 “No, I think it may make  people more aware about providing appropriate advice to their patients but I  don’t think it’s going to affect the management. That of course will be  addressed in our meeting on Anovulation Induction in London next April. “
 
 

 “The 22nd and 23rd of April  at the RCOG in London next year is going to be an ESHRE two-day meeting,  state-of-the-art, Anovulation Induction for Anovolitrium Fertility. This is a  joint venture between RCOG and ESHRE and I think it’s going to be a very popular  meeting. It’s not a consensus meeting but there will be a publication arising  from it.”
 
 

Articles

OBGYN.net Conference Coveragefrom the 19th Annual Meeting of ESHRE - Madrid, Spain

Finding a Consensus for PCOS

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       The introduction of urinary and recombinant preparations of pure  FSH for the induction of ovulation has sparked research to compare the  two with each other and with hMG in treating anovulation. For women  devoid of endogenous gonadotrophins and requiring ovulation induction,  some LH is necessary for normal ovarian steroidogenesis, but otherwise,  the LH content of hMG has little effect on clinical outcome. Any  differences found in the clinical results of the various preparations  have been insignificant in the doses used for ovulation induction,  although  recombinant FSH seems more potent.





       With the advent of ‘pure’ preparations of FSH, urinary (uFSH),  highly purified urinary (uFSH-HP) and recombinant (recFSH), several  comparative trials have been undertaken to find differences in their  effects, efficiency, results and complication rate between themselves  and compared with human menopausal gonadotrophins (hMG) in the treatment  of anovulation. These preparations have been examined in women with  hypogonadotrophic hypogonadism (H-H, WHO group I) and those with  hypothalamic-pituitary dysfunction and endogenous estrogen (WHO group  II), most of whom have polycystic ovary syndrome (PCOS). 



       Hypogonadotrophic hypogonadism is a condition with no or  unmeasurable concentrations of FSH and LH. It thus provides a unique  backdrop for the examination of the possible differences effected by the  varying concentrations of LH in these preparations. From a large trial1  utilizing recFSH and several, randomized doses of recLH for ovulation  induction in women with H-H, it is now clear that the two cell-two  gonadotrophin hypothesis is true. Follicular growth can be achieved with  FSH alone but some LH (approximately 75IU/day) is necessary to achieve  adequate steroidogenesis and efficient ovulation and luteinization in  response to hCG.

       There are several theoretical reasons for believing that pure FSH  preparations may improve efficiency and results of treatment of patients  with PCOS compared with hMG. Administration of FSH will hypothetically  correct the relative FSH deficiency and redress the high LH:FSH ratio,  both prevalent and important factors contributing to anovulation in  PCOS. In addition, pure FSH, rather than the additional LH in hMG, was  thought to be more likely to reduce the miscarriage rate and increase  chances of conception, both influenced by already high LH  concentrations. In practice, uFSH, given for ovulation induction in  PCOS, has not influenced follicular recruitment and development or  ovulation and pregnancy rates when compared with hMG2. Both FSH and hMG  decrease endogenous LH levels, FSH more than hMG, but the exogenous LH  in hMG has very little impact on endogenous levels in doses used for  ovulation induction in PCOS3. As a result, uFSH and hMG are equally  successful in inducing ovulation and no difference in pregnancy rates or  miscarriage rates has been noted. Complication rates are also similar.  The mode of administration appears to be much more important than the  preparations used; low dose therapy, be it with FSH or hMG, proving more  efficient than conventional dose therapy in preventing multiple  follicular development, multiple pregnancies and ovarian  hyperstimulation syndrome. Comparisons of uFSH with recFSH have, on the  whole, shown a greater bioactivity of recFSH for which a lower dose and  shorter duration of administration was needed4,5. No clinical advantage  in pregnancy rates was obtained with recFSH in the dose regimens used  for ovulation induction in PCOS6.

1. RECOMBINANT HUMAN LH STUDY GROUP. Recombinant human luteinizing hormone (r-hLH) to support recombinant human follicle stimulating hormone (r-hFSH) - induced follicular development in LH and FSH deficient anovulatory women: a dose finding study. J Clin Endocrinol Metab, 83, 1507-1514, 1998.

2. SAGLE M, HAMILTON-FAIRLEY D, KIDDY D, FRANKS S. A comparative, randomizd study of low dose human menopausal gonadotrophin and follicle stimulating hormone in women with polycystic ovary syndrome. Fertil Steril, 55, 56-60, 1991.

3. LARSEN T, LARSEN JF, SCHIOLER V, BOSTOFE E, FELDING C. comparison of urinary follicle stimulating hormon and human menopausal gonadotrophin for ovarian stimulation in polycystic ovary syndrome. Fertil Steril, 53, 426-431, 1990.

4. COELINGH BENNINCK HJT, FAUSER BCJM, OUT HJ. Recombinant follicle stimulating hormone (FSH;Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene resistant, normogonadotrophic chronic ovulation: a prospective, multicenter, assessor blind, randomized, clinical trial. Fertil Steril, 69, 19-25, 1998.

5. BALASCH J, FABREGUES F, PENNARUBIA J, MONTSERRAT C, VIDAL R. Follicular development and hormonal levels following highly purified or recombinant follicle stimulating hormone administration in ovulatory women and WHO Group II anovulatory infertile patients. J Assist Reprod Genet, 15, 552-559, 1998.

6. ARES-SERONO. A phase III, open, randomized, multicentre study to compare the safety and efficacy of rcombinant human follicle stimulating hormone (Metrodin) given intramuscularly, to induce ovulation in WHO Group II anovulatory infertile women. Ares-Serono Internal Report, 1995. 

The First World Congress On: Controversies in Obstetrics, Gynecology & InfertilityPrague, Czech Republic - 1999

Effects of Different Gonadotrophin Preparations in the Management of Anovulation

Research article
 		Published 14 November 2003 

Polycystic ovary syndrome [PCOS] is the commonest cause of anovulatory  infertility. Treatment modes available are numerous mainly relying on ovarian  stimulation with FSH, a reduction in insulin concentrations and a decrease in LH  levels as the basis of the therapeutic principles. Clomiphene citrate is still  the first line treatment and if unsuccessful is usually followed by direct FSH  stimulation. This should be given in a low dose protocol, essential to avoid the  otherwise prevalent complications of ovarian hyperstimulation syndrome and  multiple pregnancies. The addition of a GnRH agonists, while very useful during  IVF/ET, adds little to ovulation induction success whereas the position of GnRH  antagonists is not yet clear. Hyperinsulinemia is the commonest contributor to  the state of anovulation and its reduction, by weight loss or insulin  sensitizing agents such as metformin, will alone often restore ovulation or will  improve results when used in combination with other agents. Laparoscopic ovarian  drilling is proving equally as successful as FSH for the induction of ovulation,  particularly in thin patients with high LH concentrations. Aromatase inhibitors  are presently being examined and may replace clomiphene in the future. When all  else has failed, IVF/ET produces excellent results. In conclusion, there are  very few women suffering from anovulatory infertility associated with PCOS who  cannot be successfully treated today.
 
 


 Polycystic ovary syndrome [PCOS] is associated  with approximately 75% of women who suffer from infertility due to anovulation [1,2].  It is a very heterogeneous syndrome both in its clinical presentation and  laboratory manifestations. The majority of women with anovulation due to PCOS  have menstrual irregularities, usually oligomenorrhea or amenorrhea, associated  with clinical and/or biochemical evidence of hyperandrogenism. The main  disturbances in this syndrome are:
 
 1. Abnormal morphology of the ovary, detected by a characteristic hyperechogenic  enlarged central stroma and >9 small follicles of 2–9 mm diameter on  transvaginal ultrasound examination of the ovaries [3].

2. Abnormal steroidogenesis,  mainly increased ovarian production of androgens but also increased progesterone  and estradiol production.

3. Hyperinsulinemia, present in  about 80% of obese women and 30–40% of women of normal weight with PCOS [4]  and more strongly associated with anovulation than any other feature of the  syndrome.

4. Abnormal gonadotrophin  secretion, most commonly manifested as increased serum LH concentrations in 40%  of women with ultrasonically detected PCO [5]. A functional  deficiency of the endogenous action of FSH also seems to be present in women  with anovulatory PCOS.

Several modes of inducing  ovulation for these patients will now be described. It will be seen that they  basically depend on either a reduction of insulin concentrations, FSH  stimulation or a reduction of LH concentrations or a combination of these.


 Excess body weight is a common problem of modern  society, reaching epidemic proportions in some countries. For women with PCOS,  an excess of body fat accentuates insulin resistance and its associated clinical  sequelae. Central obesity and BMI are major determinants of insulin resistance,  hyperinsulinemia and hyperandrogenemia. The rate of insulin resistance in women  with PCOS is 50–80% and a large majority of these women are obese [6,7].

They almost inevitably have the  stigmata of hyperandrogenism and irregular or absent ovulation. Insulin  stimulates LH and ovarian androgen secretion and decreases sex hormone binding  globulin concentrations [8].

The successful treatment of  obesity and hyperinsulinemia is capable of reversing their deleterious effects,  of which there are several, on the outcome of treatment. More gonadotrophins are  required to achieve ovulation in insulin resistant women [9,10].  Obese women being treated with low dose gonadotrophin therapy have inferior  pregnancy and miscarriage rates [11]. Both obese [12]  and insulin resistant [10] women with PCOS, even on low dose  FSH stimulation, have a much greater tendency to a multifollicular response and  thus a relatively high cycle cancellation rate in order to avoid  hyperstimulation.

Just as obesity expresses and  exaggerates the signs and symptoms of insulin resistance, then loss of weight  can reverse this process by improving ovarian function and the associated  hormonal abnormalities [13-15]. Loss of weight induces a  reduction of insulin and androgen concentrations and an increase in sex hormone  binding hormone concentrations. Curiously, in obese women with PCOS, a loss of  just 5–10% of body weight is enough to restore reproductive function in 55–100%  within 6 months of weight reduction [13-15]. Weight loss has  the undoubted advantages of being effective and cheap with no side effects and  should be the first line of treatment in obese women with anovulatory  infertility associated with PCOS.


 The introduction of even small amounts of FSH  into the circulation either directly with FSH injections or indirectly with with  pulsatile GnRH or clomiphene citrate, is capable of inducing ovulation and  pregnancy in a large number of anovulatory women with PCOS. Clomiphene citrate  has long been the first line of treatment for those with absent or irregular  ovulation. It is given in a dose of 50–250 mg per day for 5 days starting from  day 2–5 of spontaneous or induced bleeding starting with the lowest dose and  raising the dose in increments of 50 mg/day each cycle until an ovulatory cycle  is achieved. In practice, I almost inevitably use a starting dose of 100 mg per  day from day 4 or 5 and have found no advantage in using a daily dose of more  than 150 mg which seems neither to significantly increase the ovulation rate nor  follicular recruitment. This sort of regimen will cut down the number of  'superfluous' cycles of treatment until ovulation is achieved and until those  resistant to clomiphene are identified. A course of 3–6 ovulatory cycles is  usually sufficient to know whether pregnancy will be achieved using clomiphene  citrate before moving on to more complex treatment as approximately 75% of the  pregnancies achieved with clomiphene occur within the first three cycles of  treatment [16].

Ovulation is restored in  approximately 80% but will result in pregnancy in only about 35–40% of patients  who are given clomiphene [16-18]. Additionally, around 20–25%  of anovulatory women with PCOS will not respond at all to clomiphene citrate and  are considered to be 'clomiphene resistant' [19,20].  Patients who do not respond to clomiphene are likely to be more obese, insulin  resistant and hyperandrogenic than those who do respond [20].  As clomiphene citrate induces a discharge of LH as well as FSH and elevated LH  concentrations are believed to impede conception, those with high basal LH  levels are also less likely to respond to clomiphene treatment [21].  The most probable factor involved in this large discrepancy between ovulation  and pregnancy rates in patients treated with clomiphene is the anti-estrogenic  effects of clomiphene at the level of the endometrium and cervical mucus. While  the depression of the cervical mucus, occurring in about 15% of patients, may be  overcome by performing intra-uterine insemination [IUI], suppression of  endometrial proliferation, unrelated to dose or duration of treatment but  apparently idiosyncratic, indicates a poor prognosis for conception in my  experience when endometrial thickness never reaches 8 mm. Monitoring of the  clomiphene treated cycle by ultrasound evaluation of follicular growth,  endometrial thickness and even estradiol and progesterone concentrations on day  12–14 of the cycle is justified by the identification of those who are not  responding or have depressed endometrial thickness and is helpful in the timing  of natural intercourse or IUI. Although this monitoring implies added expense,  this is neutralized by the prevention of protracted periods of possibly  inappropriate therapy and delay in the inception of more efficient treatment.

The results of clomiphene  treatment may be improved by co-treatment with several proposed adjuvants. The  addition of an ovulatory dose of hCG, 5,000–10,000 IU is only theoretically  warranted when the reason for a non-ovulatory response is that the LH surge is  delayed or absent despite the presence of a well developed follicle. Although  the routine addition of hCG at mid-cycle seems to add little to the improvement  of conception rates [22]. I have found it very useful, given  when an ultrasonically demonstrated leading follicle attains a diameter of 18–24  mm, for the timing of intercourse or IUI.

Daily doses of dexamethasone,  0.5 mg at bedtime, as an adjunct to clomiphene therapy, suppress the adrenal  androgen secretion and may induce responsiveness to clomiphene in previous  non-responders, mostly hyperandrogenic women with PCOS with elevated  concentrations of dehydroepiandrosterone sulphate [DHEAS] [23,24].  Although this method meets with some success, medium to long term glucocorticoid  steroid therapy often induces side effects including increased appetite and  weight gain which is not an appealing proposition for women with PCOS.

The combined treatment of  clomiphene with metformin is dealt with in the section on metformin.


 Aromatase inhibitors have been suggested as an  alternative treatment to clomiphene as the discrepancy between ovulation and  pregnancy rates with clomiphene citrate has been attributed to its  anti-estrogenic action and estrogen receptor depletion. The aromatase inhibitors  do not possess the adverse anti-estrogenic effects of clomiphene but, by  suppressing estrogen production, mimic the central reduction of negative  feedback through which clomiphene works. Letrozole, the most prevalently used  anti-aromatase for this indication, has been shown to be effective, in early  trials, in inducing ovulation and pregnancy in women with anovulatory PCOS and  inadequate clomiphene response [25] and improving ovarian  response to FSH in poor responders [26]. Evidence from larger  trials is still awaited but some encouragement may be taken from the solidity of  the working hypothesis and the success of the preliminary results.


 Gonadotrophin [FSH] therapy is usually the next step following failure with  clomiphene, i.e. there has been no response to clomiphene in a daily dose of 150  mg or 4–6 ovulatory cycles have not resulted in a pregnancy.
 
 The main complications of gonadotrophin therapy, ovarian hyperstimulation  syndrome [OHSS] and multiple pregnancies, are both caused by multiple follicular  development. Anovulatory women with PCOS are particularly prone to multiple  follicular development when receiving gonadotrophins.
 
 Acceptable cumulative conception rates have been  achieved using conventional step-up treatment with gonadotrophins for women with  PCOS. However, because of the peculiarly high sensitivity of polycystic ovaries  to gonadotrophin stimulation, this form of treatment, employing incremental dose  rises of 75 IU every 5–7 days, characteristically induces multiple follicular  development, resulting in a high frequency of multiple pregnancies and ovarian  hyperstimulation syndrome [OHSS]. A review by Hamilton-Fairley & Franks [27]  reported a mean multiple pregnancy rate of 34% and severe OHSS of 4.6%. In a  further study, although this traditional protocol produced a cumulative  conception rate of 82% after six cycles, it was plagued by an unacceptable rate  of multiple pregnancies and OHSS [28]. The supraphysiological  doses of FSH used in the conventional protocol provoke an initial development of  a large cohort, stimulate additional follicles, and even rescue those follicles  destined for atresia [29]. Levels of FSH well above the  threshold induce a multiple follicular development. While this can be utilized  for the induction of superovulation for in-vitro fertilization and embryo  transfer, for the induction of ovulation in women with PCOS the problem of  achieving the desired monofollicular ovulation is particularly difficult and  acute due to the extreme sensitivity of the polycystic ovary to gonadotrophic  stimulation. This is not due to a difference of FSH threshold levels of the  polycystic ovaries but probably to the fact that they contain twice the number  of available FSH-sensitive antral follicles in their cohort compared with the  normal ovary [30]. Any dose of FSH overstepping the threshold  of the polycystic ovary will, therefore, produce multifollicular development and  impending danger of multiple pregnancy and OHSS.

The chronic low dose regimen of  FSH was designed to reduce the rate of complications due to multiple follicular  development [For review, see ref. [31], the reasoning being  that the 'threshold theory', demanding the attainment and maintenance of  follicular development with exogenous FSH without exceeding the threshold  requirement of the ovary should be employed. The principle of the classic  chronic low dose regimen is to employ a low starting dose for 14 days and then  use small incremental dose rises when necessary, at intervals of not less than 7  days, until follicular development is initiated [32,33].  The dose that initiates follicular development is continued until the criteria  for giving hCG are attained. This form of therapy aims to achieve the  development of a single dominant follicle rather than the development of many  large follicles and thereby avoid the complications of OHSS and multiple  pregnancies.

A comparative prospective study  of the conventional regimen with chronic low dose administration of FSH for  anovulation associated with PCOS [28] involved 50  participants treated with FSH, half of them using a conventional stepwise  protocol [incremental dose rises of 75 IU every 5–7 days when necessary] and  half with a regimen of chronic low dose as described above. Both methods of  treatment had an initial dose of 75 IU FSH. Compared with the conventional dose  protocol, the chronic low dose regimen yielded slightly improved pregnancy rates  [40% versus 24%] while completely avoiding OHSS and multiple pregnancies, which  were prevalent [11% OHSS and 33% multiple pregnancies] with conventional  therapy. Uniovulation was induced in 74% versus 27% of cycles and the total  number of follicles > 16 mm and estradiol concentrations were half those  observed on conventional therapy. A large French multicentre study [34]  with an identical objective and protocol design compared conventional and  chronic low dose regimens in 103 anovulatory WHO Group II women. The comparison  of low with conventional dose revealed pregnancy rates of 33.3% versus 20%, and  with a multiple [twins] pregnancy rate of 14% and 22%, respectively. The total  number of follicles > 10 mm and estradiol concentrations on the day of hCG in  the low dose group were half those seen on conventional therapy. Additionally,  the low dose regimen tended to produce a higher rate of mono- or bifollicular  development in this study.

Reported results [31]  using a chronic low dose protocol identical to that described above, show a  remarkably consistent rate of uniovulatory cycles of around 70% and an  acceptable pregnancy rate of 40% of the patients and 20% per cycle. However, the  justification for the adoption of the chronic low dose protocol may be seen in  the almost complete elimination of OHSS and a multiple pregnancy rate of <6%.

In the normal ovulatory cycle,  decreasing FSH concentrations are seen throughout the follicular phase. In order  to mimic more closely the events of the normal ovulatory cycle, the Rotterdam  group examined a step-down dose regimen with a starting dose of 150 IU and  decreasing the dose by 0.5 ampoules when a follicle of 10 mm ensues and by the  same amount every 3 days if follicular growth continues [35,36].  A comparison of this regimen with the classic step-up regimen from the same  group [37] demonstrated a monofollicular growth rate of 88%  of cycles in the step-down regimen compared with 56% with the step-up protocol.  In the step-down group, duration of treatment and gonadotrophin requirement were  significantly reduced. However, a recently concluded randomized, French  multicenter study comparing the step-up versus the step-down protocol  demonstrated superiority of the step-up regimen as regards the rates of  monofollicular development, overstimulation and ovulation. [38].

Assuming that the step-up  protocol is superior to the step-down version, do the initial dose, the duration  of its administration and the incremental dose rise influence results? From the  largest published series of chronic low dose FSH therapy [12]  it was possible to compare the results of a starting dose of 75 IU with that of  52.5 IU for an initial 14-day period with an incremental dose rise of 37.5 IU or  22.5 IU respectively. There were no significant differences between the two  groups but pregnancy rate/patient, uni-ovulatory cycle rate and miscarriage rate  were all in favour of the smaller starting dose.

Although the majority of  patients with PCOS will reach criteria for hCG administration within 14 days  using 75 IU/day of urinary FSH [12] or 50 IU/day of  recombinant FSH, some have attempted to cut down the initial period of 14 days  without change of dose to 7 days. A comparison of 14 day versus 7 day starters [31]  in 50 patients showed no significant differences other than a slightly higher  rate of multiple pregnancies in the 7-day group. As we regarded a multiple  pregnancy as a 'failure' of treatment, we reverted back to the 14 day initial  period without any change of dose.

A recently completed multicenter  study employing a step-up protocol starting with doses of 50 IU/day of 'Puregon'  for a minimum of 7 days, compared two randomized groups using incremental dose  rises of 25 IU or 50 IU when needed [H.J. Out, personal communication]. The use  of the smaller incremental dose rises was significantly more beneficial in terms  of monofollicular development, ovulation rates and cancellation rates.

To summarise, low dose, step-up  gonadotrophin therapy should be preferred to the now outdated conventional  therapy for patients with PCOS. Small starting doses in the first cycle for a  14-day initial period without a dose change and then a small incremental dose  rise if required, seem on present evidence to give the best results.

The ability of GnRH agonists to  suppress LH concentrations before and during ovarian stimulation has earned them  an undisputed place in IVF treatment protocols. They confer the advantage of  eliminating, almost completely, the annoying occurrence of premature  luteinization. In addition, some investigators have reported more pregnancies,  possibly better quality eggs and less miscarriages [39].  Their possible application during ovulation induction should therefore be  particularly relevant in the presence of the chronic, tonic, high serum  concentrations of LH observed in a high proportion of women with PCOS.  Theoretically, by suppressing LH concentrations, GnRH agonists should eliminate  premature luteinization and alleviate the relatively low pregnancy rates and the  high miscarriage rates witnessed in this group of patients [9].  In a large study [40] 239 women with PCOS received hMG with  or without GnRH agonist for ovulation induction or superovulation for IVF/embryo  transfer. Of pregnancies achieved with GnRH agonist, 17.6% miscarried compared  with 39% of those achieved with gonadotrophins alone. Cumulative live birth  rates after four cycles for GnRH agonist were 64% compared with 26% for  gonadotrophins only.

The GnRH agonist has not become  standard treatment for ovulation induction in PCOS despite the fact that our  experience and that of others has shown an increased pregnancy rate and lower  miscarriage rate in women receiving combination treatment of agonist and  gonadotrophins when tonic LH concentrations are high [42].  There are several reasons for this apparent anachronism. Co-treatment with GnRH  agonist and low dose gonadotrophin therapy is more cumbersome, longer, requires  more gonadotrophins to achieve ovulation, has a greater prevalence of multiple  follicle development and consequently more OHSS and multiple pregnancies. This  combination therapy should be reserved for women with high serum concentrations  of LH who have repeated premature luteinization, stubbornly do not conceive on  gonadotrophin therapy alone or who have conceived and had early miscarriages on  more than one occasion.

There is no doubt that GnRH  agonists cannot help to reduce the incidence of OHSS and multiple pregnancies in  PCOS ovulation induction. If anything, combining GnRH agonist with gonadotrophin  stimulation will exacerbate the problem of multiple follicular development and  therefore increase rates of cycle cancellation, OHSS and multiple pregnancy [41,42].  This may be due to several factors: loss of the endogenous feedback mechanism  when using GnRH agonist, reduction of intra-follicular androgen levels following  pituitary down regulation and consequently postponed atresia and, most probably,  greater stimulation of follicles by the larger amounts of gonadotrophins needed  when using GnRH agonist. A GnRH agonist is not the solution to the problem of  multiple follicular development.

The two main complications of  ovulation induction for PCOS are multifollicular development and the possible  deleterious effects of high LH levels, low conception rates and high miscarriage  rates. A combination of chronic low dose FSH stimulation with GnRH agonist  therapy should theoretically therefore yield the best results. Scheele et al. [43]  studied women with PCOS undergoing ovulation induction with chronic low dose FSH  therapy, one group with and one without adjuvant GnRH agonist therapy. A very  low rate of monofollicular ovulation was achieved [14%] in the agonist cycles  compared with 44% of those treated with low dose FSH alone. Treatment with GnRH  agonist abolished neither the inter- nor intra-individual variability of the FSH  dose required to induce ongoing follicular growth but also seemed to induce an  even further increase in the sensitivity of the PCO follicles to gonadotrophin  stimulation once the threshold FSH dose had been reached.

The antagonists have some advantages  over the agonists and these may well become utilized in the treatment of  anovulatory PCOS. Firstly, antagonists act by the mechanism of competitive  binding and this allows a modulation of the degree of hormonal suppression by  adjustment of the dose. Further, antagonists suppress gonadotrophin release  within a few hours, have no flare-up effect and gonadal function resumes without  a lag effect following their discontinuation. If we apply these advantages to an  ovulation induction protocol for PCOS, one can visualize that, used in  combination with low dose FSH administration, the antagonist could be given in  single or repeated doses when a leading follicle of 13–14 mm is produced. This  would theoretically prevent premature luteinization, protect the oocyte from  deleterious effects of high LH concentrations and still allow the follicle to  grow unhindered to ovulatory size. Compared to agonist treated cycles this would  confer the, again, theoretical advantages of a much shorter cycle of treatment,  promise more conceptions and less miscarriages, reduce the amount of  gonadotrophin required and increase the incidence of monofollicular ovulation  with a consequent reduction in the prevalence of OHSS and multiple pregnancies.  Only one trial employing a GnRH antagonist with recombinant FSH, specifically  for women with PCOS, has been published to date [44].  Following pre-treatment with oral contraceptives, a GnRH antagonist was started  on in 20 patients on day 2 of the cycle. When LH concentrations were found to be  suppressed, concurrent antagonist and recombinant FSH therapy was started and  continued until the day of hCG. LH was effectively suppressed by one dose of  antagonist and all patients ovulated. Overall clinical pregnancy rates were 44%  and on-going pregnancy rates 28%. This is a preliminary trial but large RCT's  are needed to confirm these results.

The basic etiology behind the  anovulation associated with PCOS is mainly insulin resistance and  hyperinsulinemia [45,46]. This strong  association between hyperinsulinemia and anovulation would suggest that a  reduction of insulin concentrations could be of great importance. Weight loss  for the obese can reverse this situation as mentioned above but for those who  fail to lose weight or are of normal weight but hyperinsulinaemic, an insulin  sensitizing agent such as metformin is indicated. However, the indications for  the administration of metformin to anovulatory women with PCOS in an ovulation  induction program have widened as it seems to be difficult to predict which  individuals will respond well with this medication [46].  Metformin is an oral biguanide, well established for the treatment of  hyperglycaemia, that does not cause hypoglycaemia in normoglycaemic patients.  The sum total of its actions is a decrease in insulin levels and, as a  consequence, a lowering of circulating total and free androgen levels with a  resulting improvement of the clinical sequelae of hyperandrogenism.

There are now a large number of  studies published on the effect of metformin in a dose of 1500–2550 mg/day in  women with PCOS. The vast majority of these studies have demonstrated a  significant improvement in insulin concentrations, insulin sensitivity, and  serum androgen concentrations accompanied by decreased LH and increased SHBG  concentrations [48]. The restoration of regular menstrual  cycles by metformin has been reported in the large majority of published series  and the reinstatement of ovulation occurred in 78%-96% of patients [45-50].  Fleming et al [46], in the largest randomized controlled  trial published to date, demonstrated a significantly increased frequency of  ovulation with metformin as compared to placebo in a group of 92 oligomenorrheic  women with PCOS. This was achieved without any significant changes in the  insulin response to glucose challenge after 14 weeks of metformin treatment in a  dose of 850 mg, twice a day.

In a randomised controlled trial  [RCT] performed on clomiphene resistant infertile patients with PCOS, compared  with placebo, metformin markedly improved ovulation and pregnancy rates with  clomiphene treatment [51]. In a large study, 46 anovulatory  obese women with PCOS who did not ovulate on metformin or placebo for 35 days  were given 50 mg of clomiphene daily for 5 days while continuing metformin or  placebo. Of those on metformin, 19 of 21 ovulated compared with 2 of 25 on  placebo [47].

When women with clomiphene  resistant PCOS were administered FSH with or without pretreatment with metformin  for one month in an RCT, those receiving metformin developed significantly less  large follicles, produced less estradiol and had fewer cycles cancelled due to  excessive follicular development. The reduction of insulin concentrations  induced by metformin seemed to favour a more orderly follicular growth in  response to exogenous gonadotrophins for ovulation induction [52].  In the one published study on the effects of metformin on clomiphene resistant  patients undergoing IVF/ICSI, the results of cycles preceded by treatment with  metformin were compared retrospectively to those in which metformin was not  given. Those receiving metformin had a decreased total number of follicles but  no difference in the mean number of oocytes retrieved. There were more mature  oocytes, embryos cleaved, increased fertilisation and clinical pregnancy rates  [70% vs 30%] in the metformin group [53]. These latter two  studies would seem to confirm that both obese [12] and  insulin resistant [10] women with PCOS have a much greater  tendency to a multifollicular response and thus a relatively high cycle  cancellation rate on low dose FSH stimulation.

The evidence so far is  encouraging concerning the efficiency and safety of metformin as a single agent  or in combination with clomiphene citrate or gonadotrophins for induction of  ovulation in women with hyperinsulinaemic PCOS [54]. It  remains to be seen whether metformin, which probably also has a direct androgen  lowering action on the ovary, will be of help to all women with PCOS wishing to  conceive. Not only does metformin seem to be safe when continued throughout  pregnancy but preliminary data strongly suggest that this strategy can severely  decrease the high miscarriage rate usually associated with PCOS [55,56].  It is hoped that the apparent lack of terratogenicity and beneficial effect of  metformin on miscarriage rates will be confirmed by future studies.

Other compounds with the  property of lowering insulin concentrations, the glitazones rosiglitazone and  pioglitazone, and d-chiro-inositol, are under investigation and may also prove  useful for women with anovulatory PCOS


 Laparoscopic ovarian drilling [LOD] by diathermy  or laser now presents a further treatment option for women with anovulatory  infertility associated with polycystic ovary syndrome. This laparoscopic version  of ovarian wedge resection employs a unipolar coagulating current or puncture of  the ovarian surface with a laser in 4–10 places to a depth of 4–10 mm on each  ovary. An analysis [57] of the first 35 reports, mostly  uncontrolled series, showed that 82% of 947 patients ovulated following the  operation and 63% conceived either spontaneously or after treatment with  medications to which they had previously been resistant. A Cochrane data base  analysis of six randomized controlled trials [58] mostly  comparing laparoscopic ovarian drilling with gonadotrophin therapy, showed  similar cumulative ongoing pregnancy rates 6–12 months after LOD and after 3–6  cycles of gonadotrophin therapy [58]. A large, recently  completed, multicenter study in The Netherlands, showed parity in the results of  LOD and low-dose FSH therapy [Bayram et al., submitted for publication]. The  Cochrane analysis [58] highlighted the main advantage of  ovarian drilling – a very high prevalence of monofollicular ovulation and  therefore a significant reduction in multiple pregnancy rates compared with  gonadotrophin therapy. Further possible advantages of LOD are a reported  reduction in miscarriage rates [59], the fact that it is an  often successful "one-off" procedure which may avoid the use of expensive  medical therapy and the exclusion of ovarian hyperstimulation syndrome. If  ovulation is not forthcoming within 2–3 months following LOD, then ovulation  induction can often be more successfully employed than preceeding the operation.  However, in a large number of cases spontaneous ovulation has been induced even  for several years following LOD in a similar fashion to ovarian wedge resection,  the "predecessor" of LOD [60]. As LOD is less invasive and  causes less pelvic adhesions then ovarian wedge resection, there is every reason  to expect similar or even more impressive results from LOD than present evidence  suggests. Those who are slim and have high LH concentrations seem to have the  most favourable prognosis [61]. However, the mechanism  involved in the restoration of ovulation is quite unknown although the principle  endocrine change is a dramatic decrease in LH concentrations about two days  after the operation.


 If all else fails for the infertile PCOS patient  then in-vitro fertilization is a last resort providing excellent results.  Although a smaller percentage of recovered oocytes are fertilized, the larger  number of oocytes recovered from PCOS patients balances out the pregnancy rate  in comparison with, for example, women with a mechanical factor [39].  In-vitro maturation of oocytes from women with PCOS may become a possible option  [62]. However, it is proving technically difficult at present  and concerns over the well being of pregnancies achieved from IVM have not yet  been fully answered.


 Following weight loss if warranted, clomiphene  citrate is the usual first-line treatment. If clomiphene fails to induce  ovulation and pregnancy, several therapeutic paths are open depending on the  individual case: low dose FSH therapy, addition of metformin to clomiphene or  FSH treatment, laparoscopic ovarian drilling and finally, IVF. Alternative  possibilities for treatment in the near future include aromatase inhibitors and  in-vitro maturation of oocytes. Whatever the treatment option used, there are  very few women today who suffer from pure anovulatory infertility due to PCOS  who will remain involuntarily childless.

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2. 	  	Hull MG: Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies.Gynaecol Endocrinol 1987, 1:235-245.   	  	 

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6. 	  	Legro RS, Finegood D, Dunaif A: A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.J Clin Endocrinol Metab 1998, 83:2694-2698. [

7. 	  	Carmina E, Lobo RA: Polycystic ovary syndrome: arguably the most common endocrinopathy is associated with significant morbidity in women.J Clin Endocrinol Metab 1999, 84:1897-1899. [

8. 	  	Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LA: The insulin-related ovarian regulatory system in health and disease.Endocr Rev 1999, 20:535-582. [

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Polycystic ovary syndrome [PCOS] is the commonest cause of anovulatory infertility. Treatment modes available are numerous mainly relying on ovarian stimulation with FSH, a reduction in insulin concentrations and a decrease in LH levels as the basis of the therapeutic principles.

Roy Homburg, MD

Articles

Finding a Consensus for PCOS

Finding a Consensus for PCOS

Effects of Different Gonadotrophin Preparations in the Management of Anovulation

The Management of Infertility Associated With Polycystic Ovary Syndrome