Human Reproduction, Vol. 15, No. 1, 24-28,
January 2000
© 2000 European Society of Human Reproduction and Embryology
Women with polycystic ovary syndrome gain regular menstrual cycles when ageing
1 Research Institute of Endocrinology, Reproduction and Metabolism, Department of Obstetrics and Gynaecology, Polikliniek VEVO and 2 Department of Clinical Epidemiology and Biostatistics, Free University Hospital, PO Box 7057, 1007 MB Amsterdam, The Netherlands
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The aim of this study was to investigate if previously oligo- or amenorrhoeic polycystic ovary syndrome (PCOS) patients gain regular menstrual cycles when ageing. Women registered as having PCOS, based on the combination of oligo- or amenorrhoea and an increased LH concentration, were invited by letter to participate in a questionnaire by telephone. In this questionnaire we asked for the prevalent menstrual cycle pattern, which we scored in regular cycles (persistently shorter than 6 weeks) or irregular cycles (longer than 6 weeks). We interviewed 346 patients of 30 years and older, and excluded 141 from analysis mainly because of the use of oral contraceptives. The remaining 205 patients showed a highly significant linear trend (P < 0.001) for a shorter menstrual cycle length with increasing age. Logistic regression analysis for body mass index, weight loss, hirsutism, previous treatment with clomiphene citrate or gonadotrophins, previous pregnancy, ethnic origin and smoking showed no influence on the effect of age on the regularity of the menstrual cycle. We conclude that the development of a new balance in the polycystic ovary, solely caused by follicle loss through the process of ovarian ageing, can explain the occurrence of regular cycles in older patients with PCOS.
Key words: ageing/menstrual cycle/ovary/polycystic ovary syndrome
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The combination of amenorrhoea and bilaterally enlarged cystic ovaries was described for the first time in 1935 (Stein and Leventhal, 1935
). A wedge-resection of the ovaries in a series of seven patients showed in each wedge 20–100 follicular cysts of 1–15 mm. When full thickness ovarian cross-sections of polycystic ovaries were histologically examined and compared to controls it was found that polycystic ovaries had double the number of antral follicles, a thickened tunica and an increased stroma (Hughesdon, 1982). The existence of an enlarged follicle cohort in polycystic ovary syndrome (PCOS) patients was confirmed in an in-vitro fertilization (IVF) treatment (Van der Meer et al., 1998). PCOS patients developed a significantly higher number of stimulated follicles than regularly cycling control patients.
The treatment of enlarged polycystic ovaries by wedge-resection can lead to regular menstrual cycles in PCOS patients (Stein and Leventhal, 1935; Goldzieher et al., 1962; Buttram and Vaquero, 1975; Goldzieher, 1981; Dahlgren et al., 1992a). These observations led us to postulate that the enlarged antral follicle cohort is an aetiological factor in PCOS and that a decrease in size of the cohort leads to restoration of the functional balance for regular ovulatory cycles in the PCO ovary.
Ovarian ageing is known to be a process of ovarian follicle loss starting even before birth. Faddy et al. (1992) constructed a mathematical model of follicle disappearance with age on the basis of pooled data from different studies on follicle numbers in ovaries of women of different ages (Faddy et al., 1992). There appears to be a gradual loss of follicles throughout the years and from ~37 years onwards there is an accelerated decline of the remaining follicles. Another proof of a reduced follicle cohort in ageing women was documented by Friedrich et al. (1975). He punctured all visible tertiary follicles of 2–20 mm during a gynaecological operation in 65 women and found an average of six oocytes in women aged up to 40 years as opposed to only three oocytes in older women (41–53 years) (Friedrich et al., 1975).
The aim of our study was to investigate if a reduction of the antral follicle cohort due to ageing, as described by the model for follicle disappearance, also leads to regular menstrual cycles in PCOS patients.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
This study is part of a larger follow-up study of a cohort of ageing patients with PCOS called the APOS study. It was performed under the guidelines of the Helsinki Declaration of 1975 (revised version 1983) and approved by the committee for ethics of research involving human subjects of the Free University Hospital.
Patients and study design
Retrospectively, we traced all patients registered as having PCOS in the out-patient clinic of the Division of Reproductive Endocrinology and Fertility of the Free University Hospital in Amsterdam, by screening their medical charts for the combination of oligo- or amenorrhoea and an increased luteinizing hormone (LH) concentration in the presence of a normal follicle stimulating hormone (FSH) concentration.
We retrieved the current addresses of the patients by searching a computerized telephone book or by consultation of the records of municipal registry offices. We invited the patients to participate in our study by letter in which we did not mention the hypothesis: gaining regular menses with age. When the patient consented, one of the authors (T.J.M.K.) performed a structured interview by telephone. If no response was obtained to the first letter, a second mailing was sent.
Data from the charts
We screened the medical charts for the following items: dates of the first and last visit, oligo- or amenorrhoea and an elevated LH concentration, hirsutism, acne, body mass index (BMI), concentrations of FSH, prolactin, androstenedione, testosterone and oestradiol, treatment with clomiphene citrate or gonadotrophins for induction of ovulation.
Data from the questionnaire
We divided the questionnaire into several question categories as shown in Table I.
|
With respect to the hypothesis investigated in this report, we placed major emphasis on the menstrual cycle pattern. We asked the patient to describe her prevalent cycle pattern and categorized the pattern as a score from 1 to 10, as depicted in Table II
.
|
Furthermore, we asked the patient if she herself thought her menstrual cycle had changed throughout the years. If yes, she had to choose between a shorter or longer cycle and if any of the following events had led to this change: delivery, weight loss or stress.
Assays
The commercial assays used to determine LH and FSH changed in 1988 from polyclonal radioimmunoassay (Amerlex, Amersham, UK) to monoclonal radioimmunoassay (MAIA, Serono). Our endocrine laboratory tested the different assays in PCOS patients, and by means of linear regression lines found new thresholds for elevated LH and FSH concentrations. The upper limit of normal for LH changed from 12 IU/l to 6.5 IU/l, and for FSH from 12 IU/l to 10 IU/l. Later on, the MAIA assays were replaced by Amersham immunometric assays for LH and FSH which, however, did not lead to different thresholds.
Data analysis
We questioned and evaluated all patients of 30 years and older and analysed the actual menstrual cycle pattern at the time of the interview for each patient. The answer scores were categorized according to the age of the patient on the date of the interview in one of the following groups: 30–35, 36–38, 39–41, 42–45, 46–50 and 51–55 years. For analysis, we divided the cases with answer scores 1 to 5 in a regular group (score 1) and an irregular group (score 2–5). Regularity of the cycle was related to the age groups by means of a 
2 test for a linear trend. To test if the relationship between age and regularity of the cycle could be confounded by one of the following variables: BMI, weight loss, hirsutism, ethnic origin, smoking, previous treatment with clomiphene citrate or gonadotrophins, previous pregnancy and the interaction of these variables with age, we performed a forward-stepwise logistic regression analysis. For all tests the significance level was 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Response
We retrieved 556 PCOS patients from the medical charts. For 50 patients no current address could be traced. An invitation to participate and a consent form were sent to 506 patients. One hundred and two (20%) did not respond. Of the 404 (80%) who did respond, 369 (73%) agreed to participate and 35 (7%) refused. Of these 369, 21 could either not be reached by phone or appeared not to fit the diagnostic criteria of PCOS after all, and two patients were younger than 30 years of age. Finally, we interviewed 346 PCOS patients of 30 years and older.
Patients
The first visit was 12 years (mean) before the interview (range: 1.7–31.6). The patients' mean age was 26.7 years (range: 14.9–41.3) at that time. When interviewed the mean age was 38.7 years (range: 30.3–55.7). None of the patients was wedge-resected in the past.
Menstrual cycle pattern
Of the 346 patients, 121 patients (35%) used oral contraceptives (OC), 10 (3%) used hormones for infertility treatment, seven (2%) had a hysterectomy in the past, one had reached menopause and two had no cycle because they were breast-feeding. We excluded these women (141) from analysis. Of the remaining 205 patients, 123 (60%) had a menstrual cycle shorter than 6 weeks (score 1) and 82 patients had a score varying between 2 and 5. Analysis showed a strong inverse correlation between age and cycle length (P < 0.001). The proportion of women with regular menstrual cycles increased in the various age groups, from 40.6% in the group of 30–35 years to 100% in the oldest group of 51–55 years of age (Figure 1).
|
= regular, 
= irregular.The mean BMI in the regularly menstruating group (24.2) was significantly smaller than the mean of the irregular group (27.9) (Mann–Whitney test; P < 0.001). However, logistic regression analysis showed no interaction of the BMI with the effect of age on the regularity of the cycle, indicating that the relationship between age and regularity of the cycle was not influenced by the BMI. By comparing the actual BMI with the historical BMI, weight loss over the years could be calculated for 191 patients. We divided the patients into two groups: the constant weight or weight gain group, group A (n = 132) and the weight loss group, group B (n = 59). In group A 58% (77/132) had regular cycles compared to 61% (36/59) in group B, which was not significantly different (
2: P = 0.73). For this analysis we constructed one age group above 41 years of age (because of the small number of patients in the three older age groups) to gain more statistical power. The 2 tests for a linear trend for shorter menstrual cycles with increasing age were similar in both BMI groups, as depicted in Figure 2. In a logistic regression analysis weight loss did not influence the effect of age on the regularity of the cycle.
|
In the total group of 205 patients, hirsutism was more frequent in the irregularly (62.2%) than in the regularly menstruating group (48.8%), but not statistically different (P = 0.06).
Previous treatment with clomiphene citrate or with gonadotrophins for induction of ovulation did not differ between the regularly and the irregularly menstruating group (clomiphene citrate: P = 0.45, gonadotrophins: P = 0.84). Pregnancy (miscarriages and ectopic pregnancies included) occurred in 87.8% of the regularly menstruating group and in 84.1% in the irregularly menstruating group (P = 0.46). Ethnic origin or smoking habits (actual smoking or in smoking years) showed no differences between the groups. When performing logistic regression analysis for hirsutism, previous treatment with clomiphene citrate, previous treatment with gonadotrophins, previous pregnancy, ethnic origin, smoking or the interactions of these variables with age, none of the variables did influence the effect of age on the regularity of the menstrual cycle. In a step-forward logistic regression with all variables, age was the first and most significant variable, after which only BMI had some significance.
Change in menstrual cycle pattern according to the patient
Of the 205 patients, 144 answered that their menstrual cycle pattern changed, 137 (95%) found it to be shorter and seven (5%) to be longer. The remaining patients (n = 19) were not able to determine any change. Fifty patients mentioned that the pattern changed after a delivery, two after weight loss, two mentioned stress and 90 patients did not recognize any event after which the cycle pattern changed.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The results of our study show that women with PCOS gain regular menstrual cycles when ageing. This evident effect of ageing on the cycle length remains significant after correction for possible confounders such as the BMI, weight loss or hirsutism. It is known that weight loss can lead to regular menstrual cycles and spontaneous pregnancies by a more favourable ovarian environment for follicle growth through a lower insulin and insulin-like growth factor (IGF)-I concentration (Franks, 1989
; Pasquali et al., 1989; Kiddy et al., 1990, 1992). However, in our study weight losers showed the same trend for gaining regular cycles as weight gainers. The effect of ageing seems to be superior to any effect of the BMI or weight loss.
Several studies reported on the efficacy of wedge-resection in gaining regular cycles in PCOS patients. In a world-wide review of 1079 wedge-resected PCOS patients a wide range of normalization to regular cycles was reported in 6–95%, and pregnancies in 13–89% (Goldzieher, 1981) (original study: Goldzieher and Green, 1962). In another study (Buttram and Vaquero, 1975), 93.7% of 173 wedge-resected patients showed improvement of menstrual cyclicity (31.8% temporary). An explanation for this effect of wedge-resection on the menstrual cycle could be that an acute reduction of the follicle cohort leads to a new balance in the polycystic ovary between FSH and inhibin B. The combination of oligo- or amenorrhoea and the enlarged antral follicle cohort in PCOS can be caused by the production of inhibin B by antral follicles. Groome et al. (1996) found an increase in the early follicular phase of inhibin B in parallel with FSH, but with a peak value 4 days after the peak of FSH. They suggested that inhibin B might be produced by the small antral follicles as well as by the selected dominant follicle (Groome et al., 1996). The production of inhibin B by the small antral follicles is supported by the observation of mRNA production of the ß-B subunit of inhibin in these follicles (Roberts et al., 1993). As previously reported (Anderson et al., 1998; Lockwood et al., 1998), the basal inhibin B is elevated in patients with PCOS. This elevated inhibin B, produced by the enlarged antral follicle cohort, explains the relatively low FSH in women with PCOS and the stagnation of the selection process of the dominant follicle leading to arrested follicle growth and consequently cycle disturbances. A reduction in the number of antral follicles as done by wedge-resection would lead to a lower basal inhibin B concentration and consequently to a relative increase in FSH, inducing follicular growth and spontaneous ovulations. Supportive for this explanation are the findings of Lockwood et al. (1998) who treated four PCOS women with a laparoscopic diathermy and found a normalization of the inhibin B concentration post-operatively (Lockwood et al., 1998).
Dahlgren et al. (1992a) mentioned for the first time the occurrence of regular menstrual cycles in older patients with PCOS. In a long-term follow-up study she examined 33 patients of 44–59 years of age, wedge-resected 20–30 years earlier. When pre-operatively 81% and post-operatively 61% of these patients were oligomenorrhoeic, there were only 28% left to have an oligomenorrhoea in their latest decade (Dahlgren et al., 1992). This report points in the direction of the influence of age on the normalization of menstrual cycles in PCOS patients. Our study confirms this in PCOS patients not previously wedge-resected. We suggest that this phenomenon is related to the decline of the follicle cohort because of ageing (Faddy et al., 1992). Also ovarian ageing leads to a new balance between inhibin B and FSH in the early follicular phase. This can be concluded from recent publications (Klein et al., 1996; Reame et al., 1998; Welt et al., 1999) that compared FSH, inhibin A and B concentrations in the early follicular phase of older ovulatory women with that of younger ovulatory women. In all three studies the mean inhibin B concentration was significantly lower in the older women. The longitudinal study of Welt et al. (1999) showed that the decrease in inhibin B precedes that of inhibin A and appears to be the earliest marker of the decline in the follicle cohort (Welt et al., 1999).
Furthermore, the data from our study suggest that treatment with oral contraceptives in ageing women with PCOS is not always necessary, which is of clinical importance regarding the increased risk for cardiovascular disease and diabetes in women with PCOS (Mattson et al., 1984; Wild et al., 1985; Conway et al., 1992; Dahlgren et al., 1992b; Talbott et al., 1995; McKeigue, 1996).
In conclusion, our study shows that women with PCOS gain regular menstrual cycles when ageing. We suggest that the development of a new balance between inhibin B and FSH in the polycystic ovary, solely caused by follicle loss through the process of ovarian ageing, can explain the occurrence of these regular cycles. Measurements of inhibin B and FSH in older PCOS women need to be done to confirm this. Finally, our findings support the hypothesis that the enlarged antral follicle cohort is a main factor in the aetiology of the PCOS.
|
Acknowledgments |
|---|
We thank R.T.de Jongh and M.D.Kaspers, medical students, for their help in collecting data from the medical charts. This study was financially supported by Ferring b.v., The Netherlands.
|
Notes |
|---|
3 To whom correspondence should be addressed at: Free University Hospital, IVF Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Anderson, R.A., Groome, N.P. and Baird, D.T. (1998) Inhibin A and Inhibin B in women with polycystic ovarian syndrome during treatment with FSH to induce mono-ovulation. Clin. Endocrinol., 48, 577–584.[Medline]
Buttram, V.C., Jr and Vaquero, C. (1975) Post-ovarian wedge resection adhesive disease. Fertil. Steril., 26, 874.[Web of Science][Medline]
Conway, G.S., Agrawal, R., Betteridge, D. et al. (1992) Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin. Endocrinol., 37, 119–125.[Medline]
Dahlgren, E., Johansson, S., Lindstedt, G. et al. (1992a) Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focussing on natural history and circulating hormones. Fertil. Steril., 57, 505–513.[Web of Science][Medline]
Dahlgren, E., Janson, P.O., Johansson, S. et al. (1992b) Polycystic ovary syndrome and risk for myocardial infarction. Acta Obstet. Gynecol. Scand., 71, 599–604.[Web of Science][Medline]
Faddy, M.J., Gosden, R.G., Gougeon, A. et al. (1992) Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum. Reprod., 7, 1342–1346.
Franks, S. (1989) Polycystic ovary syndrome: a changing perspective. Clin. Endocrinol. (Oxf.), 31, 87–120.[Medline]
Friedrich, F., Breitenecker, G., Pavelka, R. et al. (1975) Die Morphologie der Eizellen von Blaschenfollikeln bei normaler und gestorter Eierstockfunktion der Frau. Arch. Gynak., 218, 269–280.
Goldzieher, J.W. (1981) Polycystic ovarian disease. Fertil. Steril., 35, 371–394.[Web of Science][Medline]
Goldzieher, J.W. and Green, J.A. (1962) The polycystic ovary. I. Clinical and histologic features. J. Clin. Endocrinol. Metab., 22, 325–338.
Groome, N.P., Illingworth, P.J., O'Brien, M. et al. (1996) Measurement of dimeric Inhibin B throughout the human menstrual cycle. J. Clin. Endocrinol. Metab., 81, 1401–1405.[Abstract]
Hughesdon, P.E. (1982) Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called `Hyperthecosis'. Obstet. Gynecol. Surv., 37, 59–77.[Medline]
Kiddy, D.S., Sharp, P.S., White, D.M. et al. (1990) Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin. Endocrinol. (Oxf.), 32, 213–220.[Medline]
Kiddy, D.S., Hamilton-Fairley, D., Bush, A. et al. (1992) Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin. Endocrinology, 36, 105–111.[Medline]
Klein, N.A., Illingworth, P.J., Groome, N.P. et al. (1996) Decreased Inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid concentrations of dimeric Inhibin A and B in spontaneous menstrual cycles. J. Clin. Endocrinol. Metab., 81, 2742–2745.[Abstract]
Lockwood, G.M., Muttukrishna, S., Groome, N.P. et al. (1998) Mid-follicular phase pulses of Inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle. J. Clin. Endocrinol. Metab., 83, 1730–1735.
Mattsson, L.A., Cullberg, G., Hamberger, L. et al. (1984) Lipid metabolism in women with polycystic ovary syndrome: possible implications for an increased risk of coronary heart disease. Fertil. Steril., 42, 579–584.[Web of Science][Medline]
McKeigue, P. (1996) Cardiovascular disease and diabetes in women with polycystic ovary syndrome. Baill. Clin. Endocrinol. Metab., 10, 311–318.[Web of Science][Medline]
Meer van der, M., Hompes, P.G.A., de Boer, J.A.M. et al. (1998) Cohort size rather than follicle-stimulating hormone threshold concentration determines ovarian sensitivity in polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 83, 423–426.
Pasquali, R., Antenucci, D., Casimirri, F. et al. (1989) Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J. Clin. Endocrinol. Metab., 68, 173–179.
Reame, N.E., Wyman, T.L., Phillips, D.J. et al. (1998) Net increase in stimulatory input resulting from a decrease in Inhibin B and an increase in Activin A may contribute in part to the rise in follicular phase Follicle-Stimulating Hormone of ageing cycling women. J. Clin. Endocrinol. Metab., 83, 3302–3307.
Roberts, V.J., Barth, S., El-Roeiy, A. et al. (1993) Expression of Inhibin/ Activin subunits and Follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. J. Clin. Endocrinol. Metab., 77, 1402–1410.[Abstract]
Stein, I.F. and Leventhal, M.L. (1935) Amenorrhoea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol., 29, 181–191.[Web of Science]
Talbott, E., Guzick, D., Clerici, A. et al. (1995) Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler. Thromb. Vasc. Biol., 15, 821–826.
Welt, C.K., McNicholl, D.J., Taylor, A.E. et al. (1999) Female reproductive ageing is marked by decreased secretion of dimeric inhibin. J. Clin. Endocrinol. Metab., 84, 105–111.
Wild, R.A., Painter, P.C., Coulson, P.B. et al. (1985) Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 61, 946–951.
Submitted on May 5, 1999; accepted on October 12, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Hudecova, J. Holte, M. Olovsson, and I. Sundstrom Poromaa Long-term follow-up of patients with polycystic ovary syndrome: reproductive outcome and ovarian reserve Hum. Reprod., May 1, 2009; 24(5): 1176 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Overbeek, E.A.M. Kuijper, M.L. Hendriks, M.A. Blankenstein, I.J.G. Ketel, J.W.R. Twisk, P.G.A. Hompes, R. Homburg, and C.B. Lambalk Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome Hum. Reprod., April 28, 2009; (2009) dep114v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Lockwood, G. Krikun, M. Hickey, S. J. Huang, and F. Schatz Decidualized Human Endometrial Stromal Cells Mediate Hemostasis, Angiogenesis, and Abnormal Uterine Bleeding Reproductive Sciences, February 1, 2009; 16(2): 162 - 170. [Abstract] [PDF]
|
|
|
|
 |
|
 N. B Morison, T. J Kaitu'u-Lino, I. S Fraser, and L. A Salamonsen Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives Reproduction, August 1, 2008; 136(2): 267 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The ESHRE Capri Workshop Group Endometrial bleeding Hum. Reprod. Update, September 1, 2007; 13(5): 421 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Franks Diagnosis of Polycystic Ovarian Syndrome: In Defense of the Rotterdam Criteria J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 786 - 789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.A.W. Rogers, F. Martinez, J.E. Girling, F. Lederman, L. Cann, E. Farrell, F. Tresserra, and N. Patel Influence of different hormonal regimens on endometrial microvascular density and VEGF expression in women suffering from breakthrough bleeding Hum. Reprod., December 1, 2005; 20(12): 3341 - 3347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Piltonen, L. Morin-Papunen, R. Koivunen, A. Perheentupa, A. Ruokonen, and J. S. Tapanainen Serum anti-Mullerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome Hum. Reprod., July 1, 2005; 20(7): 1820 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Legro, P. Chiu, A. R. Kunselman, C. M. Bentley, W. C. Dodson, and A. Dunaif Polycystic Ovaries Are Common in Women with Hyperandrogenic Chronic Anovulation but Do Not Predict Metabolic or Reproductive Phenotype J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2571 - 2579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G.M.G.J. Mulders, J. S.E. Laven, M. J.C. Eijkemans, F. H. de Jong, A. P.N. Themmen, and B. C.J.M. Fauser Changes in anti-Mullerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility Hum. Reprod., September 1, 2004; 19(9): 2036 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Utsunomiya, H. Ito, M. Nagaki, and J. Sato A prospective, randomized study: day 3 versus hatching blastocyst stage Hum. Reprod., July 1, 2004; 19(7): 1598 - 1603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.A. Blake, M. Proctor, and N.P. Johnson The merits of blastocyst versus cleavage stage embryo transfer: a Cochrane review Hum. Reprod., April 1, 2004; 19(4): 795 - 807. [Abstract] [PDF]
|
|
|
|
|
|
W. Sereepapong, P. Chotnopparatpattara, S. Taneepanichskul, R. Markham, P. Russell, and I. S. Fraser Endometrial progesterone and estrogen receptors and bleeding disturbances in depot medroxyprogesterone acetate users Hum. Reprod., March 1, 2004; 19(3): 547 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-P. Park, Y. J. Lee, K. S. Lee, H. A. Shin, H. Y. Cho, K. S. Chung, E. Y. Kim, and J. H. Lim Establishment of human embryonic stem cell lines from frozen-thawed blastocysts using STO cell feeder layers Hum. Reprod., March 1, 2004; 19(3): 676 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. E. Laven, A. G. M. G. J. Mulders, J. A. Visser, A. P. Themmen, F. H. de Jong, and B. C. J. M. Fauser Anti-Mullerian Hormone Serum Concentrations in Normoovulatory and Anovulatory Women of Reproductive Age J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 318 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Emiliani, A. Delbaere, A.-S. Vannin, J. Biramane, M. Verdoodt, Y. Englert, and F. Devreker Similar delivery rates in a selected group of patients, for day 2 and day 5 embryos both cultured in sequential medium: a randomized study Hum. Reprod., October 1, 2003; 18(10): 2145 - 2150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Legro Polycystic Ovary Syndrome and Cardiovascular Disease: A Premature Association? Endocr. Rev., June 1, 2003; 24(3): 302 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Virant-Klun, T. Tomazevic, B. Zorn, L. Bacer-Kermavner, J. Mivsek, and H. Meden-Vrtovec Blastocyst formation--good indicator of clinical results after ICSI with testicular spermatozoa Hum. Reprod., May 1, 2003; 18(5): 1070 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.A.K.S. Amer, Z. Banu, T.C. Li, and I.D. Cooke Long-term follow-up of patients with polycystic ovary syndrome after laparoscopic ovarian drilling: endocrine and ultrasonographic outcomes Hum. Reprod., November 1, 2002; 17(11): 2851 - 2857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.S. Macklon, M.H.E.C. Pieters, M.A. Hassan, P.H.M. Jeucken, M.J.C. Eijkemans, and B.C.J.M. Fauser A prospective randomized comparison of sequential versus monoculture systems for in-vitro human blastocyst development Hum. Reprod., October 1, 2002; 17(10): 2700 - 2705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hickey and I.S. Fraser Surface vascularization and endometrial appearance in women with menorrhagia or using levonorgestrel contraceptive implants. Implications for the mechanisms of breakthrough bleeding Hum. Reprod., September 1, 2002; 17(9): 2428 - 2434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.A.K. Amer, V. Gopalan, T.C. Li, W.L. Ledger, and I.D. Cooke Long term follow-up of patients with polycystic ovarian syndrome after laparoscopic ovarian drilling: clinical outcome Hum. Reprod., August 1, 2002; 17(8): 2035 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Van der Auwera, S. Debrock, C. Spiessens, H. Afschrift, E. Bakelants, C. Meuleman, L. Meeuwis, and T. M. D'Hooghe A prospective randomized study: day 2 versus day 5 embryo transfer Hum. Reprod., June 1, 2002; 17(6): 1507 - 1512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vanderzwalmen, G. Bertin, Ch. Debauche, V. Standaert, E. van Roosendaal, M. Vandervorst, N. Bollen, H. Zech, T. Mukaida, K. Takahashi, et al. Births after vitrification at morula and blastocyst stages: effect of artificial reduction of the blastocoelic cavity before vitrification Hum. Reprod., March 1, 2002; 17(3): 744 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Elting, J. Kwee, R. Schats, L. T. M. Rekers-Mombarg, and J. Schoemaker The Rise of Estradiol and Inhibin B after Acute Stimulation with Follicle-Stimulating Hormone Predict the Follicle Cohort Size in Women with Polycystic Ovary Syndrome, Regularly Menstruating Women with Polycystic Ovaries, and Regularly Menstruating Women with Normal Ovaries J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1589 - 1595. [Abstract] [Full Text]
|
|
|
|
|
|
M.W. Elting, T.J.M. Korsen, P.D. Bezemer, and J. Schoemaker Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population Hum. Reprod., March 1, 2001; 16(3): 556 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Balasch Investigation of the infertile couple: Investigation of the infertile couple in the era of assisted reproductive technology: a time for reappraisal Hum. Reprod., November 1, 2000; 15(11): 2251 - 2257. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||