The influence of a combined estrogen-progestin regimen (Climodien) on noopsyche, thymopsyche, personality and psychophysiological measures of menopausal syndrome patients was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3 = estradiol valerate (CAS 979-32-8) 2 mg + the progestin dienogest (CAS 65928-58-7) 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P) followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg + dienogest 2 mg) = regimen A*. 49 women (16, 17, 16 valid patients per arm) aged between 46 and 67 years (mean 58, 58, 56 years, respectively) with the diagnoses of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1) were included in the analysis of the double-blind phase. Both the double-blind and the open-label phase lasted 2 months. Noopsychic investigations demonstrated an improvement in associative verbal memory after 2 months of regimen A, which was significant as compared with both baseline and placebo. Regarding visual memory, regimen A* induced an improvement, which was significantly different from the decline in correct reproductions in the Benton Test observed under estradiol. Errors in the Benton Test decreased significantly after regimen A* as compared with regimen EV. These findings suggest that hormone replacement therapy with estradiol, and even more in combination with dienogest, improves verbal and visual memory, which is in line with the improvement in information processing speed and capacity objectified by event-related potentials (ERP). Thymopsychic investigations demonstrated a significant improvement in somatic complaints and trait anxiety after both regimen A and regimen EV as compared with baseline. State anxiety decreased significantly under regimen A* as compared with EV. The Freiburger Personality Inventory showed an improvement in aggressivity after regimen A* as compared with the preceding placebo as well as an improvement in striving after dominancy after both regimen A and regimen EV as compared with pre-treatment, but also after regimen A* as compared with regimen EV. Extraversion increased after 2 months of regimen A as compared to regimen P. Psychophysiological findings including pupillary and skin conductance variables were not significant.

Objective This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien(R)/Lafamme(R)) over 24 weeks on postmenopausal depression.Method A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) greater than or equal to 1.6 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score less than or equal to 8 (corresponding to an improvement of greater than or equal to 50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or steep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND).Results The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35).

OBJECTIVE:To study the effect on mammographic breast density of two different continuous combined regimens for hormone therapy.DESIGN:Randomized clinical study.SETTING:University hospital.PATIENT(S):Postmenopausal women without any previous history of breast disorder.INTERVENTION(S):The women received either estradiol valerate/dienogest or estradiol/norethisterone acetate. Mammograms and venous blood samples were obtained at baseline and after 6 months.MAIN OUTCOME MEASURE(S):Change in mammographic breast density. Correlations with levels of hormones, growth factors, and binding proteins.RESULT(S):An increase in mammographic density was recorded in approximately 50% of the women, and there were no differences between treatments. Increased density showed a positive correlation with estradiol, estrone, and sex hormone-binding globulin and showed a negative association to free T. Among hormonal factors, levels of free T were the most important for predicting increased density.CONCLUSION(S):Continuous combined hormone therapy with different progestogens has a marked impact on the breast.

Differences in sleep and awakening quality between 51 insomniac postmenopausal syndrome patients and normal controls were evaluated. In a subsequent double‐blind, placebo‐controlled, comparative, randomized, three‐arm trial (Climodien 2/3 = estradiol valerate 2 mg + the progestogen dienogest 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P), the effects of 2 months of hormone replacement therapy were investigated, followed by a 2‐month open‐label phase in which all patients received Climodien® 2/2 (EV 2 mg + dienogest 2 mg = regimen A*). Polysomnography at baseline demonstrated significantly deteriorated sleep initiation and maintenance, increased S1 and decreased S2 in patients. Subjective sleep and awakening quality, well‐being, morning drive, wakefulness, memory and reaction time performance were deteriorated too. Treatment with both regimen A and regimen EV induced a moderate, although nonsignificant, improvement in the primary efficacy variable wakefulness during the total sleep period compared with baseline, while under placebo no changes occurred. Secondary efficacy variables concerning sleep initiation and maintenance, and sleep architecture showed similar findings. The apnea and apnea–hypopnea indices improved significantly under regimen A, compared with both baseline and placebo. Subjective sleep and awakening quality improved significantly after regimen A and EV compared with baseline, with the drug‐induced changes being superior to those induced by placebo. In the open‐label phase, subjective sleep quality improved further, significantly in the former regimen A group. Awakening quality, somatic complaints and morning thymopsyche did not yield any significant findings. Concerning morning noopsychic performance, memory improved significantly after regimen A compared with baseline, fine motor activity after regimen EV. Reaction time performance increased with all three compounds. In conclusion, Climodien significantly improved subjective sleep quality, the apnea and apnea–hypopnea indices of insomniac postmenopausal syndrome patients, while it only marginally improved variables concerning objective sleep and awakening quality.

The basis of breast cancer risk associated with hormonal therapies may lie in the regulation of cell proliferation. In a prospective, double-blind, randomized study postmenopausal women were given continuous combined hormone replacement therapy (HRT) either as estradiol valerate 2 mg/dienogest 2 mg, (E2V/DNG) or estradiol 2 mg/noretisterone acetate 1 mg (E2/NETA) for 6 months. Fine needle aspiration (FNA) biopsies were used for immunocytochemical analysis of breast cell proliferation before and during treatment. From 45 women completing the study 135 biopsies were obtained. In the total material there was a more than 4-fold increase in proliferation between baseline and 3 months (p < 0.001). The mean percentage of MIB-1 positive breast cells increased from 2.2 to 9.1%. In some individual women values were as high as 25%. No further increase was recorded at 6 months. While numerical values were somewhat lower in the E2V/DNG group, there were no significant differences between treatments. There was a positive correlation between breast cell proliferation (MIB-1%) and circulating levels of both estradiol (rs = 0.54, p < 0.01) and estrone (rs = 0.53, p < 0.01) after 3 and 6 months of treatment. No correlations with other endogenous hormones, proteins or with the two exogenous progestogens dienogest and norethisterone were observed. Increased breast cell proliferation should probably be regarded as an unwanted side-effect during HRT. Means to identify those women with the most pronounced proliferative response should be developed. The FNA biopsy technique may be a useful tool to monitor and evaluate the proliferative response to HRT in the normal breasts of postmenopausal women.

Dienogest (17 alpha -cyanomethyl-17 beta -hydroxy-4,9-estradien-3-one) combines the benefits of norprogestogens with the typical properties of the 17 alpha -hydroxy-progesterone derivatives. Dienogest is the first representative of the so-called hybrid progestogens and is entering the hormone replacement therapy (HRT) market as a progestogenic component of the continuous combined regimen containing 2 mg 17 beta -estradiol valerate plus 2 mg dienogest daily (Lafamme(R) or Climodien(R)). Based on the pharmacodynamic profile, dienogest is suitable for combined HRT containing nonandrogenic progestogen. Preclinical and clinical studies show distinct bone protective, antiproliferative, and antiandrogenic activities. Compared with other progestogens, the portion of free, biologically available compound in the serum is very high enabling sufficient tissue penetration and additionally, there is a clear dissociation between central nervous system (CNS) and peripheral (endometrium) activities. Some of the special pharmacodynamic properties of dienogest can be explained by a "nonclassic" mode of action. This progestogen is easily transformed by different microorganisms, thus indicating no environmental risk after excretion. (C) 2001 Prous Science. All rights reserved.

OBJECTIVES:Aim was to compare the effects of estradiol-only therapy with combined estradiol/progestin treatment on the excretion of vasoactive mediators surrogating on possible effects in the vascular system. The progestin used was dienogest, a new C19-progestin with antiandrogenic properties.METHODS:Prospective, randomized trial, 25 healthy postmenopausal women treated for 3 months with estradiol valerate (2 mg/day) and 27 women with estradiol valerate (2 mg/day) continuously combined with dienogest (2 mg/day). Assessment of the following markers or their stable metabolites in nocturnal urine: cGMP, serotonin, prostacyclin and thromboxane, and urodilatin.RESULTS:Estradiol alone increased the excretion of cGMP and serotonin significantly suggesting vasodilating effects. The prostacyclin/thromboxane ratio known to be crucial for the relation of vasorelaxation to vasoconstriction significantly increased. No significant changes were found for urodilatin, which is known to elicit different effects in the cardiovascular and renal system, respectively. Combined estradiol/dienogest therapy also led to significant increases in cGMP and serotonin excretion suggesting that progestin addition for three months does not affect these markers. However, in contrast to estrogen-only treatment, there was no significant increase for the prostacyclin/thromboxane ratio, which can be explained by antagonistic action of the progestin. The excretion of urodilatin was increased significantly, which might be due to counterbalancing progestin effects in the renal vascular system.CONCLUSIONS:The changes in vasoactive markers suggest an estrogen effect that is vasorelaxant. Since there were no significant differences between the two groups, possible vascular effects of the progestin dienogest, for the first time evaluated, might not be of clinical relevance, at least not in women without cardiovascular diseases.

The fixed formulation containing 2 mg estradiol valerate and 2 mg dienogest (Lafamme(R)) has been developed for continuous hormone replacement therapy (HRT). In this paper, the clinical safety data on this drug are summarized with regard to endometrial safety, bleeding pattern, efficacy and tolerability. For the various clinical trials, healthy postmenopausal women (phase I studies) and postmenopausal women with a clinical indication for hormone replacement therapy (HRT) (phases II and III) were enrolled. All women who had started treatment were included in the safety assessment (safety population). At least 22,920 treatment cycles of 28 days each were observed, which is equivalent to 1,763 woman-years. Adverse events (AEs) documented in all studies were assessed according to conventional criteria. In two key studies, endometrial biopsies were performed. With regard to endometrial safety, the histological findings showed an atrophic endometrium in nearly 90% of the women. No hyperplastic endometrium was found in any of the women. A total of 1,834 women treated with Lafamme(R) experienced AEs which were assessed as related to the study medication. Predominant were AEs concerning the reproductive system (40.7% of the women), the central and peripheral nervous systems (10%) and the gastrointestinal system (6.7%). In total, 116 serious adverse events (SAEs) were documented, of which 29 were assessed as being related to the treatment. Both the kinds and the rates of adverse reactions documented for Lafamme(R) are already recognized in, and characteristic of, orally administered estrogen/progestogen combinations for continuous HRT (C) 2001 Prous Science. All rights reserved.

Estradiol valerate/dienogest (EV/DNG) is an oral continuous combined hormone replacement therapy (HRT) preparation containing 2.0 mg estradiol valerate and 3.0 mg dienogest, an antiandrogenic progestogen. The effects of EV/DNG (n = 43) and placebo (n = 40) on coagulation, plasma lipid profile and glucose metabolism of postmenopausal women were compared in a randomized, double-blind, multicenter study. General safety, tolerability and efficacy were also assessed. EV/DNG produced a smaller reduction in prothrombin fragments 1+2, a parameter that reflects dynamic changes in coagulation compared with placebo (31 vs. 57%; p <0.001). EV/DNG had no clinically important effects on other coagulation parameters, although moderate stimulation of fibrinolysis occurred. The effects of EV/DNG on the lipid profile were generally neutral, with significant reductions in total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol but no impact on the LDL/HDL ratio. EV/DNG did not influence glucose metabolism. Although adverse events were more common during EV/DNG treatment than placebo, they were either associated with HRT or were nonspecific. EV/DNG suppressed endometrial thickness to <5 mm, and reversed atrophic changes in the vaginal mucosa. EV/DNG was also significantly (p <0.05) more effective than placebo in relieving climacteric symptoms, particularly hot flushes, as assessed by the Kuppermann index. (C) 2001 Prous Science. All rights reserved.

This paper gives a short overview of the pharmacological and clinical profile of the sequential oral estrogen-progestogen hormone replacement drug Klimonorm (R), which contains estradiol valerate and levonorgestrel. The clinical effectiveness of Klimonorm (R) has been shown by its alleviation of classic vasomotor menopausal complaints, such as hot flushes and sweating, as well as the alleviation of some psychological symptoms, prevention of postmenopausal osteoporosis, counteraction of the symptoms and signs of urogenital atrophy, and favorable effects on lipid metabolism. Therapy with Klimonorm (R) has also resulted in stabilization of the cycle length, with a high reproducibility of cycle appearance and duration (usually 3-4 days). Cycles with regular withdrawal bleeding were restored in more than 90% of the women studied. The thickness of the endometrium, measured sonographically, did not change significantly during 3 years of therapy with Klimonorm (R). The antioxidative action of estradiol valerate was not modified in the presence of levonorgestrel. There were no clinically significant changes in body weight, blood pressure, hematological tests or parameters of clinical chemistry during Klimonorm (R) therapy. (C) 2001 Prous Science. All rights reserved.

Objective To evaluate the efficacy, safety and tolerability of continuous combined hormone replacement therapy (HRT) with Climodien® (estradiol valerate 2 mg plus dienogest 2 mg). Design Open, multinational, multicenter, non-controlled phase III study. Participants A total of 1501 women aged 52–65 years with postmenopausal symptoms of sufficient severity to require treatment. Methods Eligible patients were treated with Climodien for 12 treatment cycles (48 weeks), with assessments of efficacy, safety and tolerability (adverse events) at 8, 24 and 48 weeks. Efficacy was assessed using the Kupperman index. Safety assessments included endovaginal sonography, safety endometrial biopsies, mammography, physical and gynecological examination, vital signs, prothrombotic factors and routine laboratory safety parameters. Results The Kupperman index improved with increasing duration of treatment, accompanied by an improvement in self-reported patient well-being. Individual climacteric symptoms such as hot flushes and psychonervous disorders also improved. The most pronounced improvement was seen in women who had not previously used HRT. The incidence of breakthrough bleeding declined over time, resulting in complete amenorrhea in 86.2% of the patients after 12 cycles of treatment. Furthermore, total and low-density lipoprotein (LDL) cholesterol levels decreased and high-density lipoprotein (HDL) cholesterol levels increased. Decreases in alkaline phosphatase, pyridinoline and deoxypyridinoline demonstrated the inhibitory action of estradiol on bone resorption. Endometrial thickness remained almost constant, and the incidence of serious endometrial findings was similar to that in untreated women. Conclusions Continuous combined estrogen-progestin therapy with Climodien is effective, safe and well tolerated in postmenopausal women, with a profile and incidence of adverse events consistent with those of existing HRT preparations.

Hormone Replacement17beta-ESTRADIOLSelective Estrogen Receptor ModulatorsEstrogen SulfamatesPhytoestrogensHybrid ProgestinsSelective Progesterone ReceptorModulatorsNon-MASCULINIZING Androgen

The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.

The fixed formulation containing 2 mg estradiol valerate and 2 mg dienogest (Lafamme(R)) has been developed for continuous hormone replacement therapy (HRT) in postmenopausal women. In this review, the clinical data on pharmacokinetics, efficacy, tolerability and safety of this combination are summarized. After multiple-dose administration to postmenopausal women, estradiol and free estrone accumulated to a significantly greater extent than that predicted from single-dose data. However, total estrone accumulation was within the predicted range. The dienogest kinetics was linear and not time dependent. During the treatment of 1,500 postmenopausal patients with this formulation, the Kuppermann index as the primary target parameter of climacteric complaints, was significantly improved. The changes were independent of whether a patient had received HRT prior to joining the study and the type of HRT. In a double-blind randomized phase III study over 1 year, Lafamme(R) was found to be therapeutically equivalent to Kliogest(R) [containing 2 mg estradiol, 1 mg estriol, 1 mg norethisterone acetate (NETA)]. With regard to endometrial safety, the histological findings showed an atrophic endometrium in nearly 90% of the women. No hyperplastic endometrium was found in any of them. Adverse drug reactions (ADRs) assessed as related to therapy were reported by 1,834 women treated with this combination. Predominant were ADRs regarding the reproductive system (40.7% of the women), the central and peripheral nervous systems (10.0%), and the digestive system (6.7%). There were 116 serious adverse events, of which 29 were suggested to be drug related. The influence of Lafamme(R) on lipid parameters, surrogate parameters of vascular function, and bone-specific markers indicates favorable effects with regard to the risk of atherosclerosis and osteoporosis. (C) 2001 Prous Science. All rights reserved.

Objective To compare the efficacy and endometrial safety of two estradiol valerate/dienogest combinations with Kliogest® in the treatment of postmenopausal symptoms.Design This was a double-blind, randomized, multicenter study.Methods Patients were randomized to estradiol valerate 2.0 mg/dienogest 2.0 mg (Climodien®), estradiol valerate 2.0 mg/dienogest 3.0 mg (E2Val 2/DNG 3); or estradiol 2.0 mg/estriol 1.0 mg/norethisterone acetate 1.0 mg (Kliogest®) once daily for 1 year. The primary efficacy variable was the Kupperman index. Endometrial safety was determined primarily by biopsy.Results and Conclusions Climodien and E2Val 2/DNG 3 were therapeutically equivalent to Kliogest (mean changes in Kupperman index -20.1, -19.0 and -18.3, respectively). No statistically significant differences existed between treatment groups in the severity of postmenopausal symptoms. The incidences of endometrial atrophy were similar in all groups. Climodien appeared to be superior to Kliogest in terms of vaginal bleeding pattern, whereas E2Val 2/DNG 3 was associated with a slightly higher incidence and greater intensity of vaginal bleeding. The incidences of adverse events were similar in all groups. A greater proportion of women in the Kliogest and E2Val 2/DNG 3 groups experienced vaginal bleeding, whereas breast problems were more common with Climodien. Climodien and E2Val 2/DNG 3 induced desirable changes in insulin-like growth factor I (decrease) and sex hormone binding globulin (increase) that were not seen with Kliogest.

Objectives: To determine the progestational efficacy of continuous treatment with various doses of dienogest, combined with oestradiol valerate, on the basis of endometrial histology, effect on climacteric symptoms and bleeding profile in postmenopausal women. Methods: Patients were randomised to one of five fixed-combination treatments, oestradiol valerate 2.0 mg plus dienogest 0.5, 1.0, 2.0, 3.0 or 4.0 mg. Efficacy was assessed by endometrial biopsy, menstrual charts and change in climacteric symptoms. Results: The endometrium was classified as atrophic in 20.0, 31.3, 25.0, 55.6 and 57.1% of patients in the 0.5, 1.0, 2.0, 3.0 and 4.0 mg dienogest groups, respectively. The frequency of uterine bleeding was dose-dependent. The most favourable bleeding profile was seen in the 3.0 mg dienogest group, whereas the lower doses of dienogest had advantages with respect to the efficacy of the combined preparation. Conclusions: Dienogest 2.0 and 3.0 mg are the optimal doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone replacement therapy.

OBJECTIVE:In the present study the effect of two contraceptive pills, i.e. Neorlest, containing ethinylestradiol and norethisterone acetate, and Valette, containing ethinylestradiol and the new progestin dienogest, was investigated on the urinary excretion of vasoactive markers. As markers prostacyclin and its antagonist thromboxane, cGMP, serotonin, and the vasorelaxing mediators relaxin and urodilatin were measured.METHOD:30 women received Neorlest and 33 women Valette in a randomized, open, parallel-group study design. Nocturnal urine was collected before treatment and during cyclic treatment after 6 and 11 weeks.RESULTS:For prostacyclin, the ratio of prostacyclin to thromboxane, relaxin and urodilatin significant increases compared to the pretreatment values were observed with Valette within 11 weeks treatment. For the markers cGMP and serotonin both contraceptive pills showed a tendency to an increase of the renal excretion after 11 weeks treatment. No significant differences between the two pills were observed, except in the case of the ratio of prostacyclin to thromboxane, which showed a significant, clear-cut enhancement with Valette.CONCLUSION:These results indicate that contraceptive pills may stimulate the production of vasodilative markers, an effect which can be attributed most likely to the oestrogenic component of the pill. The progestogenic component of the pill may elicit an impact on this oestrogen-induced vasodilation, which, however, seems to be minimized in the case of the new compound dienogest, a C-19 progestin with antiandrogenic properties.

International Journal of Gynecology & ObstetricsVolume 70, Issue S3 p. C23-C23 Free communication effects of HRT Efficacy and safety of a combination of 2 mg estradiol valerate plus 2 mg dienogest in postmenopausal women T. Graser, T. GraserSearch for more papers by this authorT. Romer, T. RomerSearch for more papers by this authorF. Walter, F. WalterSearch for more papers by this authorM. Oettel, M. OettelSearch for more papers by this author T. Graser, T. GraserSearch for more papers by this authorT. Romer, T. RomerSearch for more papers by this authorF. Walter, F. WalterSearch for more papers by this authorM. Oettel, M. OettelSearch for more papers by this author First published: 10 December 2003 https://doi.org/10.1016/S0020-7292(00)81476-9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume70, IssueS32000Pages C23-C23 RelatedInformation

The effects of two oral contraceptive combinations, dienogest 2.0 mg plus ethinyl estradiol 0.03 mg (Valette) and desogestrel 0.15 mg plus ethinyl estradiol 0.02 mg (Lovelle), on the human immune system were compared over one treatment cycle of 31 patients (n = 15 and n = 16, respectively). Lovelle but not Valette significantly increased the numbers of lymphocytes, monocytes and granulocytes. Valette decreased CD4 lymphocytes after 10 days' treatment; Lovelle had the opposite effect. Lovelle increased CD19 and CD23 after 21 days' treatment. Phagocytic activity was unaffected by either treatment. After 10 days' treatment, both contraceptives reduced serum IgA, IgG and IgM, which remained lowered at day 21 with Lovelle but returned to baseline with Valette. Secretory IgA was unaffected by either contraceptive. Neither treatment affected levels of interleukins, except for a significant difference between the treatment groups for interleukin-6 after 10 days' treatment that disappeared after 21 days' treatment. Levels of non-immunoglobulin serum components fluctuated; macroglobulin was increased with Valette. However, total protein and albumin levels were reduced more with Lovelle than with Valette. Complement factors also fluctuated. There was no evidence for any sustained immunosuppression with either Valette or Lovelle.