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European Journal of Endocrinology (2005) 152 411–418 ISSN 0804-4643

CLINICAL STUDY Late administration of mifepristone suppresses circulating leptin and FSH – mechanism(s) of action in ? Riikka Leminen1, Taneli Raivio2,3, Sirpa Ranta4, Joachim Oehler5, Helena von Hertzen6, Olli A Ja¨nne2,7 and Oskari Heikinheimo1,4 1Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland, 2Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland, 3Hospital for Children and Adolescents, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, 4Biomedicum Helsinki, Institute of Biomedicine/Biochemistry, University of Helsinki, Helsinki, Finland, 5The Concept Foundation, Bangkok, Thailand, 6WHO, UNDP/UNFPA, Geneva, and 7Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (Correspondence should be addressed to O Heikinheimo, Department of Obstetrics and Gynaecology, University of Helsinki, PO Box 140, FI-00029, HUS, Finland; Email: oskari.heikinheimo@helsinki.fi)

R Leminen and T Raivio contributed equally to this work

Abstract Objective: Low dose mifepristone (RU486) is highly effective in emergency post-coital contraception (EC), although the mechanism(s) of action remains unclear. We studied the endocrine actions of 10 mg mifepristone administered orally as a single dose to eight healthy volunteers (aged 20–45 years) during the late follicular phase. Methods: Serum levels of LH, FSH, oestradiol, , leptin, mifepristone, , and gluco- corticoid bioactivity (GBA) were measured before and 1, 2, 4 and 8 h after ingestion of mifepristone on cycle day 10 or 11 (study day 1), and follow-up was continued for 10 days. Ovarian ultrasono- graphy was performed on study days 1 and 7. Similar measurements were carried out during a con- trol cycle. Results: Mifepristone postponed , as evidenced by a 3.4^1.1 day (means^S.D.) delay (P , 0.005) in the LH surge and 3.6^4.0 day prolongation of the treatment cycle (P ¼ 0.08). During the mifepristone cycle, an LH surge was displayed by five subjects when serum mifepristone levels had declined to 9.5^7.1 nmol/l. During the day of mifepristone administration, circulating GBA (P , 0.001) and leptin (P , 0.001) levels declined. On the day after mifepristone adminis- tration, mean serum FSH and leptin levels were lower than pretreatment values (3.8^1.8 IU/l vs 5.2^1.1 IU/l, n ¼ 7, P , 0.05; 28.9^6.7 mg/l vs 33.2^9.0 mg/l, n ¼ 7, P , 0.05 respectively), and the corresponding difference in the mean serum oestradiol concentration was borderline (452^252 pmol/l vs 647^406 pmol/l, n ¼ 7, P ¼ 0.056). In contrast to the control cycle, individual leptin levels declined during the follow-up after ingestion of mifepristone (n ¼ 8, P , 0.01). Conclusions: These data showed that the commonly employed dose of mifepristone for EC delays ovu- lation and prolongs the menstrual cycle, when given during the late follicular phase. The mechanism of action of mifepristone may include a reduction of FSH secretion via a decrease in circulating leptin.

European Journal of Endocrinology 152 411–418

Introduction no change (7) or a slight decline in circulating gonado- trophin levels (6). Following preovulatory adminis- Emergency post-coital contraception (EC) with mife- tration of 10 mg mifepristone, the luteinizing pristone is highly efficient (1–4). It was estimated hormone (LH) surge was retarded for 2–5 days in that single doses of 10, 50 or 600 mg mifepristone pre- some subjects and was not detectable in others (8). vented 84–86% of in a multicentre trial Thus, inhibition or a delay of ovulation is probably (4). The action of mifepristone in EC is likely to involve the most important single factor mediating the effect several mechanisms, both endocrine and endometrial of this drug in EC (9). (5). Investigations evaluating the effects of late follicu- The mechanism by which mifepristone perturbs ovu- lar phase administration of mifepristone (6–8) have lation remains unclear, especially as the drug is capable revealed arrested follicular growth and a decrease in of inhibiting both and progesterone serum oestradiol concentration associated with either receptors; both signalling pathways may have direct

q 2005 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.01884 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 09/28/2021 06:01:43PM via free access 412 R Leminen, T Raivio and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 or indirect effects on gonadotrophin secretion. For without mifepristone. However, samples equivalent to example, both progesterone and are those taken at 1–8 h in the mifepristone cycle were involved in the regulation of circulating leptin concen- not collected on day 1 during the control cycle. The trations which, in turn, may modify the timing of time of blood sampling varied between 0700 and ovulation. The role of leptin appears to be age depen- 1905 h. The control cycle and the mifepristone cycle dent, because the (pre)pubertal rise in circulating were separated by a minimum of one regular menstrual leptin concentrations in adolescent girls is associated cycle. The subjects kept a diary of their menstrual with maturation of the hypothalamic–pituitary–ovar- cycles. The study protocol was approved by the Insti- ian axis and may act as a signal for the initiation of tutional Review Board of Helsinki University Central menstrual cycles (10, 11). After establishment of ovula- Hospital and the Finnish National Agency for Medi- tory cycles, leptin is thought to have at least a permiss- cines. Pharmacokinetic data concerning 10 mg mife- ive role in ovulation (12). In adult women, serum leptin pristone have been published elsewhere (21). concentrations increase during the luteal phase of the cycle (13–15) and during the follicular phase after Transvaginal ultrasonography administration of progesterone (16). On the other hand, leptin is also regulated by glucocorticoids (17). Transvaginal ultrasonography (US) was carried out in For example, increases circulating all participants on day 1, and again on day 7, during leptin concentrations in both men and women, and both the control and mifepristone-treated cycles in stimulates secretion of leptin from cultured adipocytes order to measure the diameter of the largest follicles (18, 19). Anti-glucocorticoid effects of mifepristone on in both ovaries. A Hitachi EUB-550 scanner (Hitachi adipose tissue lipoprotein lipase activity have been Medical Corporation, Tokyo, Japan) with a 6.5 MHz demonstrated previously by Ottosson et al. (20). To the vaginal transducer was used. best of our knowledge, the effect of mifepristone on cir- culating leptin concentrations in humans and the sub- Hormone assays sequent timing of ovulation has not been investigated. The purpose of this work was to characterize the Serum LH, follicle-stimulating hormone (FSH), prog- endocrine effects of mifepristone given during the late esterone and cortisol concentrations were measured follicular phase that potentially contribute to its by time-resolved fluoroimmunoassays. Commercial action in EC. In particular, we have hypothesized that kits (DELFIA), manufactured by Perkin Elmer Life mifepristone may perturb ovulation in part by suppres- Sciences (Turku, Finland) were used. The detection sing circulating leptin concentrations. limits reported by the manufacturer were 0.05 U/l for both LH and FSH, 0.8 nmol/l for progesterone and 15 nmol/l for cortisol. The intra-assay and interassay Materials and methods coefficients of variation (C.V.) were 2.0–2.4% and Subjects 3.1–4.2% for LH, 2.0–2.8% and 1.8–2.0% for FSH, 3.3–7.3% and 2.7–10.1% for progesterone and 4.5– Eight healthy women between 20 and 45 years of age 7.0% and 3.5–5.0% for cortisol respectively. Oestradiol volunteered for the study. They all had regular men- concentrations were determined by RIA according to strual cycles, with cycle length varying between 25 the protocol from the World Health Organization and 32 days. None of them used hormonal contracep- (22). The quantitation limit of the RIA (55 pmol/l) is tion: four were sterilized, one used a copper-releasing the lowest concentration that can be measured with and the remaining three used bar- acceptable precision (i.e. intra-assay C.V. #20%). The rier methods. All were of normal weight, with body intra-assay C.V. varied from 4.3 to 7.4% and the inter- mass index varying from 19 to 26 kg/m2. Prior to assay C.V. from 7.9 to 16.6%. Serum levels of mifepris- their participation in this study, each woman signed tone were measured by RIA preceded by Chromosorb an document. column chromatography (Sigma, St. Louis, Missouri, USA), as described previously (23). The quantitation Protocol limit of the assay was 0.36 nmol/l. The intra-assay C.V. was 8.4% and the interassay C.V. varied from Following an overnight fast, a single dose of 10 mg 10.3 to 13.6%. An immunoradiometric assay (IRMA) mifepristone (supplied by Hualian Pharmaceuticals was used to measure serum leptin concentrations. Co. Ltd, Shanghai, China) was ingested on day 10 or The commercial IRMA kits were manufactured by 11 of the menstrual cycle. On the day of mifepristone Diagnostic Systems Laboratories Inc. (Webster, Texas, administration (day 1), venous blood samples were col- USA). The detection limit was 0.10 ng/ml. The intra- lected in the morning before (0730–0930 h) and 1, 2, assay and interassay C.V. values varied from 2.6 to 4 and 8 h after ingesting the drug, daily thereafter for 4.9% and 3.7 to 6.6% respectively. the next 6 days and then on day 11. The same blood Glucocorticoid bioactivity (GBA) was measured sampling protocol was repeated during a control cycle directly from 10 ml serum samples using a recombinant

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Table 1 Day of the LH peak, cycle length and AUCs for progesterone (P4) and oestradiol (E2) between days 1 and 7 of the control and mifepristone cycles. The data are derived from the seven subjects who ovulated during the control cycle and are expressed as means^S.D. LH peaks during the follow-up period in the mifepristone cycle were recorded in five subjects.

LH peak (cycle day) Cycle length (days) AUC P4 (nmol/l per day) AUC E2 (pmol/l per day) Control cycle 12.7^2.4 26.1^3.3 64.2^55.3 3375^862 Mifepristone cycle 14.8^0.8† 29.7^3.5 20.3^15.8 2797^1393 Difference between the cycles 3.4^1.1† 3.6^4.0 P value 0.003 0.08 0.06 0.58

† Based on the five subjects who displayed surges of LH secretion following mifepristone administration; their LH peaks occurred on cycle day 11.4^1.4 during the control cycle. cell bioassay in which COS-1 cells are transfected with brief, linear regression lines were fitted for each individ- expression vectors encoding human glucocorticoid ual with the day of the cycle as an independent variable and a co-regulator, ARIP3, and serum leptin concentration as a dependent vari- together with an appropriate reporter gene (24). In able. The areas under the concentration curves the current work, GBA values less than 15.6 nmol/l (AUCs) for serum oestradiol and progesterone were cal- cortisol equivalents were considered undetectable. culated using the trapezoidal rule (26). The AUCs and slopes of the leptin equations were subsequently com- Data analyses pared by means of the paired t-test. A P value of #0.05 was considered significant. Ovulation was defined to have taken place following an LH peak if an increase in progesterone of 10 nmol/l was measured and/or if signs of preceding follicular rupture Results were seen in US performed on study day 7. Correlations Effects of mifepristone on the menstrual cycle between various parameters were assessed by simple regression. Paired t-tests and ANOVA for repeated We examined the effects of a low dose of mifepristone measurements followed by Scheffe’s post hoc analysis given during the late follicular phase of the menstrual were used when appropriate. To investigate the changes cycle in healthy women who were followed-up during in serum leptin concentrations during the follicular a control cycle and a mifepristone treatment cycle. phase of the control and mifepristone cycles, the We examined eight women and evidence of ovulation method of summary measures (25) was employed. In during the control cycle was found in seven. The

Figure 1 Serum FSH, LH, oestradiol, progesterone and mifepristone levels during the late follicular phase of a control cycle (no medication; left-hand panels) and the mifepristone cycle (10 mg mifepristone on cycle day 10; right-hand panels) in a representative subject.

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Downloaded from Bioscientifica.com at 09/28/2021 06:01:43PM via free access 414 R Leminen, T Raivio and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 subject who did not ovulate during the control cycle was removed from further analysis of the effects of mife- pristone on the menstrual cycle. Data related to the timing of ovulation during the two cycles, together with the AUCs for oestradiol and progesterone between days 1 and 7 in these seven subjects are given in Table 1. The delay in the LH surge appeared to be dependent on mifepristone concentration, because LH peaks exceeding 25 IU/l became evident in five subjects only after circulating mifepristone levels had declined to 9.5^7.1 nmol/l (means^S.D.). Figure 1 shows the cir- culating FSH, LH, oestradiol, progesterone and mife- pristone levels during the two menstrual cycles in a representative subject. Administration of 10 mg mife- pristone on cycle day 10 prolonged her menstrual cycle from 25 to 28 days; her LH peak was postponed by 2 days. Figure 2 shows circulating FSH and LH levels (means^S.D.) during the control and treatment cycles among the seven subjects who ovulated during the con- trol cycle; in addition, serum mifepristone concen- trations are shown. Serum levels of FSH were significantly different (P , 0.01, two-way ANOVA) during days 1–4 of the control and mifepristone cycles, whereas those of LH approached significance (P ¼ 0.1, two-way ANOVA). During the mifepristone cycle, the decline in serum FSH from day 1 to day 2 was statistically significant (P , 0.05). Serum pro- gesterone levels were significantly different (P , 0.01, two-way ANOVA), whereas those of oestradiol were not distinguishable (data not shown) between the two cycles during days 1 to 4. Transvaginal US was performed twice during the control and mifepristone cycles. The diameter (means^ S.D.) of the dominant follicle measured on study day 1 did not differ between the control and mifepristone cycles (14.5^4.4 vs 12.4^3.2 mm respectively). During the mifepristone cycle, the dominant follicle that had been visualized on day 1 persisted in three Figure 2 Means^S.D. levels of FSH, LH and mifepristone during of the seven subjects, whereas ovulation had occurred the control (open symbols) and mifepristone (solid symbols) treat- prior to day 7 in the remaining four subjects. The size ment cycles. The decline in serum FSH from day 1 to day 2 of the dominant follicle and the delay in the LH surge during the mifepristone cycle was statistically significant during the mifepristone cycle were not correlated. (P , 0.05).

Effects of mifepristone on circulating GBA (P 0.0001, ANOVA) was accompanied by a decrease and leptin , in circulating leptin concentrations (P , 0.001, On the day of mifepristone administration, circulating ANOVA) (Fig. 3B). On the day after mifepristone admin- GBA levels were rapidly suppressed close to, but istration, the mean serum leptin level was lower than above, the detection limit of the bioassay (Fig. 3A), the 0 h (pretreatment) value (28.9^6.7 mg/l vs whereas there was no evidence of a compensatory 33.2^9.0 mg/l, n ¼ 7, P , 0.05). increase in serum cortisol occurring on the same day Individual serum mifepristone levels during the days or the day following mifepristone administration following mifepristone ingestion are shown in Fig. 4A (Fig. 3A). At approximately noon, GBA values during and the individual profiles for serum leptin during the mifepristone cycle and those observed without the control cycle and mifepristone cycle are shown medication began to overlap, indicating that relatively in Fig. 4B. We next compared the changes in short suppression of GBA is brought about by 10 mg serum leptin concentrations during the control and mifepristone (Fig. 3A). This suppression of GBA mifepristone cycles by fitting linear regression lines for

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Figure 3 (A) Serum GBA and cortisol concentrations plotted against the time of day during the control cycle without mifepristone (left), on the day of ingestion of 10 mg mifepristone (middle) and on the day after mifepristone ingestion (right) in eight healthy women. Linear regression lines are shown. Small solid circles in right panel of (A) indicate highest and lowest individual values. (B) Circulating levels of GBA (upper panel) and leptin (lower panel) (means^S.D.) on the day of ingestion of 10 mg mifepristone. *P,0.05, **P , 0.001, ***P , 0.0001 compared with pretreatment (0 h) values (ANOVA for repeated measures followed by Scheffe’s post hoc analysis). each woman with leptin values from both cycles with mifepristone exceeded 10 nmol/l for approximately 4 the day of the cycle as an independent variable and days, which is well in line with the observed pro- serum leptin concentration as a dependent variable. longation of the menstrual cycle following mifepristone There was a significant difference (P , 0.01) between administration. Thus, when counselling women the slopes of the regression lines between the control requesting mifepristone for EC, the risk of unintended and mifepristone cycles (Fig. 4B). To ensure that this later during the same cycle needs to be difference was not caused by diurnal variation in considered. leptin, we adjusted serum leptin levels for the time of In this work, we found that administration of mife- day (serum leptin concentration divided by the corre- pristone was followed by a statistically significant sponding time of the day) and repeated the regression decline in serum FSH levels, which was associated analyses. After this procedure, the difference between with a similar, albeit non-significant, change in serum the cycles remained significant (Fig. 4B; P , 0.05). oestradiol concentrations. A decline in circulating oes- tradiol levels after preovulatory administration of mife- pristone associated with either a slight decline or a lack Discussion of normal FSH increase has been reported previously (6, 7). Thus, prolongation of the follicular phase and In the present study, we have demonstrated, as also the subsequent delay in ovulation brought about by shown previously (6–8), that preovulatory adminis- mifepristone may occur via suppression of FSH. tration of mifepristone to healthy women interrupts The precise mechanism(s) by which mifepristone the final stages of follicular development and postpones affects the timing of ovulation has remained enigmatic. ovulation. Typical characteristics of mifepristone action Mifepristone has been shown not to alter the pattern of in EC are a dose-dependent delay in the subsequent pulsatile secretion of LH (6, 7) or pituitary responsive- menstrual period and a risk of unintended pregnancy ness to gonadotrophin-releasing hormone (GnRH) in cases of further unprotected intercourse following (28). Mifepristone possesses both anti-progestogenic use of the drug (3, 27). The relationship between circu- and anti-glucocorticoid properties, and their roles in lating mifepristone concentration and inhibition of ovu- the timing of ovulation have been investigated pre- lation has not been previously assessed in women. viously. For example, co-administration of dexametha- Among the present subjects, LH peaks were apparent sone and mifepristone during the late follicular phase when the mean circulating mifepristone level had does not abolish the mifepristone-induced inhibition declined to a mean of 9.5 nmol/l. Serum levels of of ovulation in cynomolgus monkeys (29). In healthy

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Figure 4 (A) Serum mifepristone levels in eight healthy women following ingestion of 10 mg mifepristone. (B) Individual serum leptin levels during the control cycle and mifepristone cycle in eight healthy women (upper panels). Leptin levels adjusted for the time of day are shown in the lower panels. (Box plots) Respective distributions of the slopes of leptin change during the control and mifepristone cycles. *P , 0.05, **P , 0.01. women progesterone has been shown to reverse the On the other hand, we found that mifepristone midcycle effects of mifepristone (30). Thus, the ability significantly modified circulating levels of leptin. of mifepristone to perturb ovulation and FSH secretion Accumulating evidence suggests that leptin is an is thought to be a result of the anti-progestogenic effect. important modulator of the timing of menstrual

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Downloaded from Bioscientifica.com at 09/28/2021 06:01:43PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 Preovulatory effects of low-dose mifepristone 417 cycles. For example, in laboratory animals, leptin is 2 Webb AMC, Russell J & Elstein M. Comparison of , known to regulate GnRH secretion via neuropeptide Y , and mifepristone (RU486) in oral postcoital contracep- tion. British Medical Journal 1992 305 927–931. (31, 32), and administration of exogenous leptin to 3 WHO TaskForce on Postovulatory Methods of Fertility Regulation. fasting rodents and monkeys prevents suppression of Comparison of three single doses of mifepristone as emergency gonadotrophin secretion (31, 32). In humans, adminis- contraception: a randomised trial. Lancet 1999 353 697–702. tration of leptin to a girl with a leptin gene mutation 4 von Hertzen H, Piaggio G, Ding J, Chen J, Song S, Bartfai G, Ng E, resulted in gradual activation of gonadotrophin Gemzell-Danielsson K, Oyunbileg A, Wu S, Cheng W, Ludicke F, Pretnar-Darovec A, Kirkman R, Mittal S, Kho-massurdze A, secretion (33), and leptin is suggested to regulate the Axter D & Peregondov A. Low dose mifepristone and two nocturnal LH profile in the mid- to late follicular regimens of for emergency contraception: a WHO phase that precedes ovulation (34). Although adipo- multicentre randomised trial. Lancet 2002 360 1803–1810. cytes express progesterone receptors (35), progesterone 5 Croxatto HB, Devoto L, Durand M, Ezcurra E, Larrea F, Nagle C, does not stimulate leptin secretion of cultured adipo- Ortiz ME, Vantman D, Vega M & von Herzen H. Mechanism of action of hormonal preparations used for emergency contracep- cytes (36). On the other hand, expression and release tion: a review of the literature. Contraception 2001 63 of leptin from adipose tissue is stimulated by glucocor- 111–121. ticoids (18, 19, 37). We found that mifepristone 6 Liu J, Garzo G, Morris S, Stunkel C, Ulmann A & Yen SS. Disrup- induced a profound suppression of circulating GBA, tion of follicular maturation and delay of ovulation after adminis- tration of the antiprogesterone RU486. Journal of Clinical and have previously shown that the concentrations of Endocrinology and Metabolism 1987 65 1135–1140. mifepristone in serum and adipose tissue after a single 7 Croxatto H, Salvatierra A, Fuentealba B & Leiva L. Follicle stimu- ingested dose are similar (38). Thus, the observed sup- lating hormone-granulosa cell axis involvement in the antifollicu- pression of leptin in the current work probably reflected lotrophic effect of low dose mifepristone (RU486). Human an anti-glucocorticoid effect of mifepristone in fat, simi- Reproduction 1995 10 1987–1991. 8 Marions L, Hultenby K, Lindell I, Sun X, Sta˚bi B & Gemzell- lar to that previously demonstrated with cultured adi- Danielsson K. Emergency contraception with mifepristone and pocytes (39). It is of note that healthy women in the levonorgestrel: mechanism of action. Obstetrics and Gynecology mid- to late follicular phase of the menstrual cycle dis- 2002 100 65–70. play an increase or no change in leptin around noon 9 Gemzell-Danielsson K, Mandl I & Marions L. Mechanisms of (34), whereas we found that leptin declined during action of mifepristone when used for emergency contraception. Contraception 2003 68 471–476. the day of mifepristone ingestion. We cannot therefore 10 Hardie L, Trayhurn P, Abramovich D & Fowler P. Circulating exclude the possibility that, in humans, suppression of leptin in women: a longitudinal study in the menstrual cycle circulating leptin concentrations following ingestion and during pregnancy. Clinical Endocrinology 1997 47 101–106. of mifepristone contributes to the subsequent and 11 Apter D. The role of leptin in female adolescence. Annals of the transient decrease in gonadotrophin secretion. New York Academy of Sciences 2003 997 64–76. 12 Moschos S, Chan JL & Mantzoros CS. Leptin and reproduction: a In conclusion, late follicular phase administration of review. Fertility and Sterility 2002 77 433–444. 10 mg mifepristone delayed or inhibited ovulation in all 13 Riad-Gabriel M, Jinagouda S, Sharma A, Boyadjian R & Saad M. subjects. Mifepristone may postpone ovulation via Changes in plasma leptin during the menstrual cycle. European several endocrine mechanisms, suppression of circulat- Journal of Endocrinology 1998 139 528–531. ing FSH being the most probable. The mechanisms that 14 Teirimaa T, Luukkaa V, Rouru J, Koulu M & Huupponen R. Corre- lation between circulating leptin and luteinizing hormone during lead to gonadotrophin suppression following mifepris- the menstrual cycle in normal-weight women. European Journal of tone may involve changes in circulating leptin. Endocrinology 1998 139 190–194. 15 Cella F, Giordano G & Cordera R. Serum leptin concentrations during the menstrual cycle in normal weight women: effects of an oral triphasic estrogen-progestin medication. European Journal Acknowledgements of Endocrinology 2000 142 174–178. 16 Messinis IE, Papageorgiou I, Milingos S, Asprodini E, Kollios G & We wish to thank Ms Pirkko Timonen for her pro- Seferiadis K. Oestradiol plus progesterone treatment increases fessional handling of the volunteers and Ms Marjatta serum leptin concentrations in normal women. Human Reproduc- Tevilin for her expert laboratory work. Financial sup- tion 2001 16 1827–1832. port from Helsinki University Central Hospital Research 17 Askari H, Liu J & Dagogo-Jack S. Hormonal regulation of human Funds and from the Concept Foundation is gratefully leptin in vivo: effects of and insulin. International Journal of Obesity 2000 24 1254–1259. acknowledged. O H is a recipient of a Finnish Medical 18 Masuzaki H, Ogawa Y, Hosoda K, Miyawaki T, Hanaoka I, Foundation Clinical Fellowship grant. The contents of Hiraoka J, Yasuno A, Nishimura H, Yoshimasa Y, Nishi S & the present manuscript do not necessarily reflect the Nakao K. Glucocorticoid regulation of leptin synthesis and policy of any of the funding sources. secretion in humans: elevated plasma leptin levels in Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism 1997 82 2543–2547. 19 Halleux CM, Saervais I, Reul BA, Detry R & Brichard SM. 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