December 28, 2007
Cyclical Dydrogesterone in Secondary Amenorrhea: Results of a Double- Blind, Placebo-Controlled, Randomized Study
By Panay, Nicholas Pritsch, Maria; Alt, Jeannette
Abstract Secondary amenorrhea in women with normal estrogen levels increases the risk of endometrial carcinoma. Cyclical dydrogesterone induces regular withdrawal bleeding and effectively protects the endometrium of postmenopausal women receiving estrogens. In order to assess the efficacy of dydrogesterone in inducing regular withdrawal bleeds in premenopausal women with secondary amenorrhea or oligomenorrhea and normal estrogen levels, a double-blind, randomized, placebo-controlled, multicenter study was conducted in 104 women using cyclical dydrogesterone as is used for estrogen replacement therapy. Treatment consisted of dydrogesterone (10 mg/day on days 1-14 followed by placebo on days 15-28 of each cycle) given for six cycles of 28 days. The control group received placebo throughout the six cycles. Bleeding was documented by the patient on diary cards. The number of women with withdrawal bleeding during the first cycle was twice as high in the dydrogesterone group as in the placebo group (65.4% vs. 30.8%; p = 0.0004). Superiority of dydrogesterone was also observed for regularity of bleeding over the six cycles (p
Keywords: Secondary amenorrhea, oligomenorrhea, withdrawal bleeding, bleeding pattern, dydrogesterone
Secondary amenorrhea broadly refers to the cessation of menses once menstruation has been established. It has, however, been specifically defined in various ways, some of which overlap with oligomenorrhea (infrequent menstrual flow at intervals of 35 days to 6 months), thus reflecting the diffuse patient populations who suffer from this condition. The overall prevalence of secondary amenorrhea in women of menstruating age is around 3% [1,2], although it is considerably more common in certain subgroups such as competitive athletes, gymnasts and ballet dancers [3,4]. Amenorrhea is a symptom rather than a diagnosis and is indicative of anatomical, genetic or neuroendocrine abnormalities. The majority of cases, however, are related to ovarian dysfunction.
Patients with secondary amenorrhea may be more likely to develop endometrial hyperplasia or endometrial cancer, notably those with normal or high endogenous estrogen levels and luteal insufficiency [5-7]. This increased risk was demonstrated in a study of 2496 infertile women, followed-up for a mean period of 21 years, in which the observed number of endometrial cancers in those with normal estrogen production but progesterone deficiency was 9.4-fold higher than that expected in normal women . Inadequate progesterone production due to lutealphase insufficiency in the presence of normal or elevated estrogen levels may have a number of causes, such as anovulatory cycles in menarche or menopause, or polycystic ovary syndrome (PCOS). PCOS is the most common endocrine disorder in women; approximately 20% of premenopausal women will show ovarian cysts on an ultrasound scan and up to 10% will have symptoms [8,9].
The endometrium can be protected from the proliferative effects of estrogen by progestogens. Dydrogesterone is a retroprogesterone that is used in a number of indications including dysfunctional uterine bleeding, endometriosis and threatened and habitual abortion, as well as in combined hormone replacement therapy (HRT). Sequential administration of dydrogesterone (10 mg/day) for 14 days per 28-day cycle has been shown to be highly effective in protecting the endometrium in postmenopausal women receiving estrogen replacement and to result in regular withdrawal bleeding [10-16].
Dydrogesterone is available as Duphaston(R) tablets containing 10 mg dydrogesterone and is currently indicated to treat secondary amenorrhea in combination with an estrogen once daily from day 1 to day 25 of the cycle, and a dosage of 10 mg dydrogesterone twice daily from day 11 to day 25 of the cycle. The aim of the present study was to compare the efficacy of sequential dydrogesterone with that of placebo in inducing regular withdrawal bleeding in premenopausal women with secondary amenorrhea or oligomenorrhea and normal estradiol levels. The chosen dose is known to effectively protect the endometrium of postmenopausal women on estrogen replacement. This is the first double-blind, placebo-controlled, randomized study to assess dydrogesterone-induced bleeding in this population.
This double-blind, randomized, placebo-controlled, parallel- group, multicenter (12 centers in Germany, Austria and Switzerland) study was carried out in 104 premenopausal women with secondary amenorrhea (cessation of bleeding for at least 50 days without pregnancy) or oligomenorrhea (infrequent menstrual flow at intervals of 35 days to 6 months, documented for at least four of the previous six cycles). The patients were aged between 20 and 50 years old, had premenopausal levels of endogenous estrogen (> 30 pg/ml) and follicle-stimulating hormone (FSH) (6 mm (bilayer). Exclusion criteria included clinically relevant disease that might limit participation in or completion of the study, any gynecological neoplasia or anatomical abnormality, icterus or pruritus during previous pregnancies, Herpes gestationis, a positive pregnancy test, breastfeeding, severe drug allergy or history of severe abnormal drug reactions towards a progestogen, intake of any investigational product in the previous 12 weeks or former participation in a study with dydrogesterone, use of a progestogen in the previous 3 months or other hormones or antidiabetics in the previous month.
All patients provided written informed consent. Patients were advised that the treatment was non-contraceptive. The protocol was approved by the Independent Ethics Committee or Institutional Review Board of each centre and the study was conducted in accordance with the Declaration of Helsinki and ICH guidelines for Good Clinical Practice.
Treatment and assessments
Following a screening period of maximum duration 2 weeks, the patients were randomized to receive sequential oral dydrogesterone 10 mg/day from day 1 to day 14 (followed by placebo from day 15 to day 28 of each cycle) or placebo for 24 weeks. The active medication, as well as the placebo, was presented as cyclical treatment with red encapsulation during the first 2 weeks of the cycle and white capsules during the second half of the cycle. In vitro release rates did not show a clinically relevant reduction of release rates due to the encapsulation. Randomization was performed in blocks of four at a ratio of 1:1. Patients who had spontaneous bleeding during the screening period started medication 15 days after the first day of bleeding, while those who did not experience bleeding started medication on the day of randomization (day 1). Concomitant treatment with antidiabetics, insulin, sex hormones, barbiturates or rifampicin was not permitted.
Physical and gynecological examinations, transvaginal ultrasound scan (TVUS), and measurement of vital signs and laboratory parameters (pregnancy test, urinalysis, blood chemistry, and blood levels of FSH, estradiol and progesterone) were performed at the start of the screening period. Demographic and baseline data, medical history and any concomitant medications were also recorded. On the day of randomization, the patients were given a diary containing three daily diary cards to complete during cycles 1 to 3 (day 1-84) and were instructed on the correct ways to document drug intake (yes/no), vaginal bleeding and body temperature measured with an ear thermometer. Vaginal bleeding was recorded as follows: 0 = no bleeding, 1 = spotting (not requiring sanitary protection), 2 = slight bleeding, 3 = normal bleeding and 4 = severe bleeding. TVUS, pregnancy test, measurement of vital signs and blood estradiol and progesterone levels, and recording of baseline complaints and concomitant medication were also repeated at the randomization visit.
Assessments were performed on day 28 (i.e. after one cycle of treatment), day 84 (after three cycles) and day 168 (after six cycles). TVUS, pregnancy test, measurement of vital signs and plasma progesterone, and recording of concomitant medication, compliance and any adverse events were performed at each visit. The first diary was collected on day 84 and a new diary for use during cycles 4 to 6 (day 84-168) was handed out. This second diary was collected on day 168. Blood chemistry and urinalysis were repeated on days 84 and 168, while physical and gynecological examinations and measurement of body weight and plasma estradiol were performed on day 168.
The primary efficacy variable was the occurrence (yes/no) of withdrawal bleeding during the first treatment cycle. Bleeding episodes were defined as one or more successive days with a severity of bleeding coded as >0. According to World Health Organization conventions , two bleeding episodes separated by a single day without bleeding, or by a day on which bleeding information was missing, were regarded as a single episode. A bleeding episode was defined as withdrawal bleeding if it occurred between days 12 and 28 of the cycle, lasted at least three consecutive days with a maximum gap of one day, and had a bleeding intensity of at least 1 (spotting). To test the null hypothesis of a lower or equal rate of withdrawal bleeding in the dydrogesterone group compared with placebo against the alternative hypothesis of a higher rate of withdrawal bleeding, the one-sided Fisher's exact test was used. The significance level was fixed to a = 0.025.
Sample size was determined as follows. Based on published data, the expected percentage of patients with withdrawal bleeding was 70% with dydrogesterone. The expected percentage with placebo was in the range of 30-35%. When the level of significance was set to 0.05 and the power to 80%, the number of patients required to complete each treatment arm was 24 to 31. Taking into account an expected dropout rate of 25%, the total number of patients required to investigate the primary efficacy variable was 84. In addition, in order to gain an insight into the regularity of bleeding in the cycles following the first withdrawal bleeding, it was decided to recruit 100 patients.
The intention-to-treat (ITT) population used in the analysis of the primary endpoint comprised all randomized patients; those with missing data or missing diaries were considered as 'failures'. The secondary efficacy variable was the regularity of bleeding pattern during the six cycles of the study. The ITT population for this analysis included all randomized patients who had documented data in the diary for at least five cycles (drug intake and bleeding data). The regularity of bleeding with an intensity of at least 2 (slight bleeding) was scored by an index for each cycle as follows: an index of 1 if the episode was within an interval of 28 days (+- 4 days) of a bleeding episode in the previous cycle, and an index of 0 if no episode occurred or if the start of the episode was not within an interval of 28 days (+- 4 days) after an episode in the previous cycle. The indices of all cycles were added together, resulting in a score ranging from 0 (absence of bleeding) to 6 (regular bleeding during all six cycles). These regularity scores were compared between groups using the Mann-Whitney U test.
Further exploratory analyses were performed to compare the effects of dydrogesterone and placebo on endometrial thickness, to determine the effects of stratification by secondary amenorrhea and oligomenorrhea, and to evaluate any correlation between endometrial thickness and bleeding pattern and between the starting day of bleeding episodes and their regularity. The basis of these evaluations was the ITT population. Comparisons between the groups were carried out by the Mann-Whitney U test or the Kruskal-Wallis test in cases of ordinal or continuous data, and by the Fisher's exact test in the case of categorical data. The Spearman rank correlation was used to describe correlations between ordinal or continuous data. For within-group comparisons, the Wilcoxon matched pairs signed rank test was used for continuous data. All tests in the exploratory analyses were carried out two-sided and a result with a p value of
All randomized women who received at least one dose of study medication were included in the safety analysis. Safety parameters included adverse events, vital signs, physical examination findings, body weight, TVUS, concomitant medication, laboratory tests and body temperature.
The distribution of patients during the study is shown in Figure 1. A total of 104 patients were randomized to treatment, 52 in each group. The baseline and demographic characteristics of these patients are shown in Table I; there were no relevant differences between the groups. The study was completed by 47 patients in the dydrogesterone group and 42 in the placebo group. The main reason for withdrawal was loss to follow-up (two patients in the dydrogesterone group and seven in the placebo group). Adverse events accounted for the withdrawal of two patients given dydrogesterone (one for heavy erratic bleeding and one for increase in body weight) and three given placebo (one pregnancy/miscarriage, one pregnancy/ hyperemesis and one increase in body weight). One patient in the dydrogesterone group withdrew due to lack of effect. All 104 patients were included in the ITT analysis of the primary efficacy variable and in the safety analyses (Figure 1). Analyses of the secondary efficacy variables did not account for six patients in the dydrogesterone group and 13 in the placebo group due to missing diaries.
Figure 1. Distribution of patients.
The number of women with withdrawal bleeding during the first cycle of treatment was twice as high in the dydrogesterone group as in the placebo group (65.4% vs. 30.8%; p = 0.0004). The 95% confidence interval for the difference was 16.6-52.6%). Dydrogesterone was therefore superior to placebo with regard to the primary efficacy variable. In a sensitivity analysis where the definition of withdrawal bleeding was changed from bleeding for at least three consecutive days to at least two or four days, dydrogesterone remained superior to placebo. If the definition of withdrawal bleeding was changed from bleeding for at least three consecutive days with intensity of at least 1 to intensity of at least 2, the withdrawal bleeding rate was 32.7% in the dydrogesterone group and 25.0% in the placebo group (p = 0.52). If the definition was further changed to bleeding intensity of at least 3, the rates were 23.1%) vs. 3.9%, respectively (p = 0.008).
Table I. Demographic and baseline characteristics.
During the six cycles of treatment, the percentage of patients who experienced bleeding episodes of any type was consistently higher with dydrogesterone than with placebo (Figure 2). In both groups, however, the incidence of bleeding was highest in the first cycle of treatment. The mean duration of the bleeding episodes was longer in the dydrogesterone group than in the placebo group in each of the six cycles (Table II).
The regularity of bleeding (regularity score) was better in patients treated with dydrogesterone than in those given placebo (median regularity score: 4.0 vs. 1.0; p 0 compared with 21 patients (53.8%) in the placebo group (Figure 3). Regular bleeding in at least four cycles was achieved in more than half of the dydrogesterone-treated patients (n = 27; 58.7%) but in only a fifth of placebo-treated patients (n = 8; 20.5%). Nine patients (19.6%) in the dydrogesterone group and two (5.1%) in the placebo group experienced regular bleeding in all six cycles; the regularity score by number of patients is shown in Table III. There was less variability in the starting day of bleeding in patients treated with dydrogesterone compared with placebo.
Figure 2. Percentage of patients with bleeding episodes per cycle during treatment with dydrogesterone (n = 52) or placebo (n = 52) (intention-to-treat (ITT) population).
Table II. Duration (days) of bleeding episodes per cycle during treatment with dydrogesterone or placebo (intention-to-treat population).
Figure 3. Regularity score per patient of treatment with dydrogesterone (n = 46) or placebo (n = 39) (intention-to-treat population).
Table III. Regularity score by number of patients during treatment with dydrogesterone or placebo (intention-to-treat population; n = 85).
Comparing the subgroups of patients with secondary amenorrhea (n = 79) and oligomenorrhea (n = 25) with respect to demographic and baseline parameters revealed significantly (p = 0.004) more patients with endocrinological disorders in the oligomenorrhea subgroup (8; 33.3%) than in the secondary amenorrhea subgroup (6; 10.2%). With the exception of one patient with oligomenorrhea, all patients with endocrinological disorders were suffering from thyroid disease (most commonly hypothyroidism). The uterine cavity was also longer (median: 34.0 vs. 29.0 mm; p = 0.036) and the endometrium thicker (median: 10.0 vs. 8.0 mm; p = 0.015) in women with oligomenorrhea. There were no other significant differences between the two subgroups with regard to demographic and other baseline characteristics.
Although estradiol levels were within the normal range in both subgroups, the incidence of bleeding during the first cycle in both treatment groups combined was significantly higher in patients with oligomenorrhea (17; 68.0%) than in those with secondary amenorrhea (33; 41.8%) (p
Median endometrial thickness, measured at baseline and at the end of treatment cycles 1, 3 and 6, decreased from baseline to the final visit with dydrogesterone (8.2 to 6.0 mm; p
Endometrial thickness and bleeding
A correlation between endometrial thickness and the maximum bleeding intensity in the following cycle was observed for endometrial thickness measured at baseline and after one and three cycles of treatment. The effect was seen in both the dydrogesterone and placebo groups and was most pronounced in the baseline measurement with the following first treatment cycle (Table IV). The correlation between endometrial thickness and maximum bleeding intensity in the previous cycle was weaker. The findings were similar if the sum of the bleeding intensity over the 28 days of the cycle was analyzed in place of the maximum bleeding intensity.
Safety and tolerability
Dydrogesterone was well tolerated. There were no serious adverse events in the dydrogesterone group; the three pregnancies in the placebo group (one of which was associated with severe hyperemesis and another resulted in miscarriage) were classified as serious adverse events. Treatment-emergent adverse events were reported in 12 patients (23%) treated with dydrogesterone (19 events) and 13 patients (25%) given placebo (16 events). The most common events were infection (n = 3), back pain (n = 2) and depression (n = 2) in the dydrogesterone group and flu (n = 3), unintended pregnancy (n = 3) and abdominal pain (n = 2) in the placebo group. All other events were reported no more than once in each group. There were no clinically significant differences between the groups with regard to vital signs, laboratory values, body temperature, body weight, TVUS or physical examination findings. The body temperature did not change significantly during the study in either group.
In women with secondary amenorrhea, normal or elevated estrogen levels in combination with inadequate progesterone can increase the risk of endometrial hyperplasia or cancer. In women with amenorrhea or oligomenorrhea, the induction of artificial withdrawal bleeding with a progestogen is therefore considered prudent management of these patients. The results from this study show that sequential dydrogesterone, 10 mg/day on days 1-14 of each cycle, has statistically significant advantages over placebo with regard to the induction of withdrawal bleeding and the regularity of the bleeding. The percentage of patients experiencing withdrawal bleeding during the first cycle was 65.4% in the dydrogesterone group and 30.8% in the placebo group. These values were close to the incidence assumed for the original sample size calculation. The percentage of patients with bleeding was highest during the first cycle and tended to fall thereafter in both groups. Although there were a significant number of 'withdrawal' bleeds in the placebo group, the regularity of bleeding throughout the study was markedly better in the dydrogesterone group. Regular bleeding during at least four cycles was achieved in more than half of the patients treated with dydrogesterone compared with only around a fifth of those given placebo. The fact that the body temperature did not change during the study indicates that there was no increase in endogenous progesterone levels in either group.
Table IV. Correlation between endometrial thickness and the maximum bleeding intensity in the following cycle: baseline endometrial thickness and following first cycle of treatment.
A number of previous studies have also demonstrated that dydrogesterone induces a withdrawal bleed in women with secondary amenorrhea providing the endometrium is sufficiently primed with estrogens. With the exception of one double-blind, randomized study showing that dydrogesterone was as effective as medroxyprogesterone acetate in inducing withdrawal bleeding , the majority of these studies were uncontrolled [19-23] and employed a different dosage regimen to that used in the current study. There is, nevertheless, considerable evidence from the use of combined HRT showing that dydrogesterone 10 mg/day given for 14 days per 28-day cycle effectively protects the endometrium from the proliferative effects of estradiol and results in regular and predictable withdrawal bleeding [10-16].
A placebo effect on bleeding, similar to the one noted in the current study, has been previously described. A response rate of 30% was reported in women with secondary amenorrhea and/or persistent oligomenorrhea and adequate estrogen production, providing the placebo was accompanied by positive suggestion [24,25]. In another study involving 56 women with secondary amenorrhea, oral or intramuscular placebo resulted in bleeding in 48% of the women . The majority of the responders had at least two cyclical bleeding episodes and the beneficial effects stopped once the placebo had been withdrawn. A subgroup analysis in this study demonstrated, however, that the incidence of bleeding during placebo treatment is much higher in oligomenorrhoeic women than in those with secondary amenorrhea (63.6% vs. 22.0%). It appears that patients with oligomenorrhea may have a higher propensity to menstruate spontaneously. Differences were also seen with regard to the regularity of bleeding, with the clear significant advantages of dydrogesterone over placebo observed in patients with secondary amenorrhea not being observed in those with oligomenorrhea. This may be accounted for by the more frequent spontaneous bleeding in the oligomenorrhea group.
There was evidence of a correlation between endometrial thickness and bleeding intensity, but the correlation was not consistently reflected in monotonously increasing medians and the value of endometrial thickness as a predictor of subsequent bleeding was low. Although previous studies have indicated that progestogen-induced withdrawal bleeding can indeed be predicted from the endometrial thickness, there is a wide variation in the cut-off points identified in the different studies and the predictive value is not very good [18,27-29]. In addition, in contrast to previous studies, patients were included in the current study only if they had normal estradiol levels, thus excluding those with an insufficiently stimulated endometrium. The clinical value of using endometrial thickness as a predictor of bleeding in an individual patient must therefore be considered limited.
Endometrial thickness was reduced with both dydrogesterone and placebo, with no significant differences between the groups. However, a more marked reduction occurred with dydrogesterone than with placebo in the subgroup of patients with oligomenorrhea. It should be noted that the sample size was determined based on the expected percentage of patients with withdrawal bleeding, and the study was not designed to analyze endometrial thickness. The small number of patients in this subgroup therefore weakens the statistical result of this exploratory analysis.
Exploratory analyses revealed a number of other differences between patients with secondary amenorrhea and those with oligomenorrhea. For example, the endometrium was thicker in women with oligomenorrhea, which might reflect greater estrogenic stimulation, although the estradiol levels were within the normal range in both subgroups. The incidence of withdrawal bleeding during the first cycle was also higher in the oligomenorrhea subgroup, which again points towards greater stimulation of the endometrium. Comparison of the baseline characteristics of the two subgroups showed that there were significantly more patients with a history of thyroid disorders in the oligomenorrhea subgroup. Thyroid disorders are known to be associated with changes in estrogen and androgen metabolism, impaired fertility and menstrual disorders . For example, auto-immune thyroiditis is about three times more common in patients with PCOS than in the general population . Similarly, around a quarter of patients with hypothyroidism or hyperthyroidism suffer from some form of menstrual disorder, oligomenorrhea and hypomenorrhea being the most common.
In conclusion, the results of this study showed that dydrogesterone is significantly superior to placebo in inducing withdrawal bleeding in women with secondary amenorrhea and that the pattern of this bleeding is significantly more regular with dydrogesterone, while adverse events are no different from those seen with placebo.
We would like to thank the following investigators: Dr Eisinger (Berlin), Dr Frank (Munich), Dr Herold (Munich), Dr Ihm (Munich), Dr Jakubek (Berlin), Dr Kranzlin (Munich), Dr Peschke (Berlin), Dr Lindecke (Berlin) and Dr Michel (Diessen) in Germany; Dr Musfeld (Binningen) and Dr Scott (Trimbach) in Switzerland; and Dr. Potsch (Leibnitz) in Austria.
1. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2004;82(Suppl 1):S33-S39.
2. Speroff L, Fritz MA. Amenorrhea. In: Speroff L, Fritz MA, editors. Clinical gynecologic endocrinology and infertility. 7th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2005. pp 401-464.
3. De Souza MJ, Metzger DA. Reproductive dysfunction in amenorrhoeic athletes and anorexic patients: a review. Med Sci Sports Exerc 1991;23:995-1007. 4. Klentrou P, Plyley M. Onset of puberty, menstrual frequency, and body fat in elite rhythmic gymnasts compared with normal controls. Br J Sports Med 2003;37:490- 494.
5. Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, Oelsner G, Freedman L, Mashiach S, Lunenfeld B. Cancer incidence in a cohort of infertile women. Am J Epidemiol 1998;147:1038-1042.
6. Gibson M. Reproductive health and polycystic ovary syndrome. Am J Med 1995;98:67S-75S.
7. Balen A. Polycystic ovary syndrome and cancer. Hum Reprod Update 2001;7:522-535.
8. Birdsall MA, Farquhar CM. Polycystic ovaries in pre and post- menopausal women. Clin Endocrinol (Oxf) 1996;44: 269-276.
9. Farquhar CM, Birdsall M, Manning P, Mitchell JM, France JT. The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust N Z J Obstet Gynaecol 1994;34:67-72.
10. van der Mooren MJ, Hanselaar AGJM, Borm GF, Rolland R. Changes in the withdrawal bleeding pattern and endometrial histology during 17beta-estradiol-dydrogesterone therapy in postmenopausal women: a 2-year prospective study. Maturitas 1994;20:175-180.
11. Burch DJ, Spowart KJW, Jesinger DK, Randall S, Smith SK. A dose-ranging study of the use of cyclical dydrogesterone with continuous 17beta-oestradiol. Br J Obstet Gynaecol 1995;102:243- 248.
12. Ferenczy A, Gelfand MM. Endometrial histology and bleeding patterns in postmenopausal women taking sequential combined estradiol and dydrogesterone. Maturitas 1997;26: 219-226.
13. Bergeron C, Fox H. Low incidence of endometrial hyperplasia with acceptable bleeding patterns in women taking sequential hormone replacement therapy with dydrogesterone. Gynecol Endocrinol 2000;14:275-281.
14. van de Weijer PHM, Scholten P, van der Mooren MJ, Barentsen R, Kenemans P. Bleeding patterns and endometrial histology during administration of low dose estradiol sequentially combined with dydrogesterone. Climacteric 1999;2:1-9.
15. Ferenczy A, Gelfand MM, van de Weijer PHM, Rioux JE. Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17beta-oestradiol combined with sequential 5-20 mg dydrogesterone. Climacteric 2002;5:26-35.
16. Gelfand MM, Fugere P, Bissonnette F, Wiita B, Yang H-M, Lorrain J, Ferenczy A. Conjugated estrogens combined with sequential dydrogesterone or medroxyprogesterone acetate in postmenopausal women: effects on lipoproteins, glucose tolerance, endometrial histology and bleeding. Menopause 1997;4:10-18.
17. Belsey EM, Machin D, D'Arcangues C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. Contraception 1986;34:253-260.
18. Battino S, Ben-Ami M, Geslevich Y, Weiner E, Shalev E. Factors associated with withdrawal bleeding after administration of oral dydrogesterone or medroxyprogesterone acetate in women with secondary amenorrhoea. Gynecol Obstet Invest 1996;42:113-116.
19. Bernard I. New progesterone derivatives active by the oral route. Bull Fed Soc Gynecol Obstet Lang Fr 1962;14:683-684.
20. Rockenschaub A. On the problem of oral therapy in menstrual disorders. Wien Klin Wochenschr 1962;74:285-287.
21. Bompiani A, Moneta E. Progestational activity of isopregnolone in cases of secondary amenorrhoea. Ann Ostet Ginecol 1962;84:607-621.
22. Tillinger KG, Diczfalusy E. Progestational activity of stereoisomeric progesterone-analogues following oral administration in amenorrhoea. Acta Endocrinol (Copenh) 1960;35:197-203.
23. Serfaty D, Nahmanovici C, Thompson N, Le Gral M. Traitement symptomatique des ameorrhees secondaires par la dydrogesterone. A propos d'une etude propective et multicentrique. Gaz Med Fr 1986;93:81-84.
24. Presl J, Horsky J. Uterine bleeding as a placebo effect. Cesk Gynekol 1970;35:413-415.
25. Presl J, Bechinie K, Horsky J. The possibility of placebo effect in the progesterone test. Cesk Gynekol 1970;35:409-412.
26. Crosignani PG, Mattei AM, Maggioni P, Testa G, Negri E. Efficacy of placebo in the treatment of patients with amenorrhea. Gynecol Obstet Invest 1994;37:183-184.
27. Nakamura S, Douchi T, Oki T, Ijuin H, Yamamoto S, Nagata Y. Relationship between sonographic endometrial thickness and progesrin- induced withdrawal bleeding. Obstet Gynecol 1996;87:722-725.
28. Morcos RN, Leonard MD, Smith M, Bourguet CB, Makii M, Khawli O. Vaginosonographic measurement of endometrial thickness in the evaluation of amenorrhea. Fertil Steril 1991;55:543-546.
29. Shulman A, Shulman N, Weissenglass L, Bahary C. Ultrasonic assessment of the endometrium as a predictor of oestrogen status in amenorrhoeic patients. Hum Reprod 1989;4:616-619.
30. Krassas GE. Thyroid disease and female reproduction. Fertil Steril 2000;74:1063-1070.
31. Janssen OE, Mehlmauer N, Hahn S, Offher AH, Gartner R. The high prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Eur J Endocrinol 2004; 150: 363-369.
This paper was first published online on iFirst on 19 September 2007
NICHOLAS PANAY1, MARIA PRITSCH2, & JEANNETTE ALT3
1 The Menopause and PMS Centre, Queen Charlotte's & Chelsea Hospital and Westminster Hospitals, London, UK,
2 Department of Medical Biometry, University of Heidelberg, Heidelberg, Germany, and 3 Solvay Pharmaceuticals,
(Received 4 July 2007; revised 18 July 2007; accepted 18 July 2007)
Correspondence: N. Panay, The Menopause and PMS Centre, Queen Charlotte's & Chelsea Hospital, Hammersmith Hospitals NHS Trust, Du Cane Road London, West London, UK. Tel: 44 20 8383 3513. Fax: 44 20 8383 3521. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Nov 2007
(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.