Progesterone in Peri- and Postmenopause: A Review.

! Around 14.5 million peri- and postmenopausal women currently live in Germany. Moreover, ap- proximately 450 000 women, each with a life ex- pectancy of around 85 years, reach menopause every year in Germany. The challenge is therefore to find a therapy with few side effects which could improve the quality of life of women with menopausal symptoms. The aim of hormone therapy (HT) is to remedy hormone deficiencies using substances that offer the best trade-off between benefits and risks. This is where proges- terone has a new and important role to play. Pro- gesterone is one of the most important gestagens. Biologically effective progesterone formulations created with micronization techniques have been used in clinical practice since 1996. Nevertheless, up until 2003 preference was given to synthetic gestagens rather than progesterone. The in- creased breast cancer hazard ratio of 1.23 re- ported in the WHI study and of 2 given in the Mil- lion Women Study has been associated with the use of synthetic gestagens. In a comparison be- tween synthetic gestagens and progesterone, the E3N Study showed that the transdermal adminis- tration of estrogen and progesterone did not lead to an increase in breast cancer rates (RR: 1.08). The administration of progesterone does not change the HDL/LDL cholesterol ratio. Because of its anti-mineralocorticoid effect, progesterone has no impact on carbohydrate metabolism, he- mostasis, blood pressure, thrombogenicity and body weight. The administration of 200 mg/day progesterone over 12 days of a menstrual cycle or a daily administration of 100 mg combined with an estrogen are a safe and well-tolerated op- tion to treat menopausal symptoms, with a better benefit risk profile compared to synthetic gesta- gens. Zusammenfassung ! Aktuell leben 14,5 Millionen peri- und post- menopausale Frauen in Deutschland. Gleichzeitig gibt es ungefähr 450 000 neue menopausale Frau- en pro Jahr, die eine Lebenserwartung von bis zu 85 Jahren haben. Die Herausforderung besteht daher in einer möglichst nebenwirkungsarmen Therapie bei den Frauen mit menopausalen Be- schwerden, um einer Verschlechterung ihrer Le- bensqualität entgegenzuwirken. Ziel einer Hor- montherapie (HT) sollte die Behebung des Hor- monmangels sein, wobei Substanzen mit dem besten Nutzen-Risiko-Profil eingesetzt werden sollten. Hier spielt Progesteron eine neue und wichtige Rolle. Beim Progesteron handelt es sich um den wichtigsten Vertreter der Gestagene. Durch Mikronisierungsverfahren können biolo- gisch wirksame Formulierungen hergestellt wer- den, sodass es seit 1996 Anwendung im kli- nischen Alltag findet. Dennoch wurde bis 2003 den synthetischen Gestagenen und nicht dem Progesteron der Vorzug gegeben. Die Erhöhungen des Mammakarzinomrisikos in der WHI-Studie auf eine Ratio von 1,23 und in der Million-Wom- en-Studie auf bis zu 2 sind daher auch unter die- sem Aspekt zu werten. Beim Vergleich zwischen synthetischen Gestagenen und Progesteron konn- te in der E3N-Studie gezeigt werden, dass es unter einer transdermalen Östrogengabe zusammen mit Progesteron nicht zu einer Erhöhung der Mammakarzinomrate (RR von 1,08) kommt. Pro- gesteron verändert nicht die HDL/LDL-Choleste- rinratio. Es hat keinen Einfluss auf den Kohlenhy- dratstoffwechsel, die Hämostase, den Blutdruck, die Thrombogenität und das Körpergewicht, da es auch antimineralokortikoid wirkt. Die Gabe von 200 mg Progesteron pro Tag über 12 Tage im Zyklus oder die tägliche Gabe von 100 mg in Kom- bination mit einem Östrogen stellen daher eine sichere Option in der Behandlung der menopau- Progesterone in Peri- and Postmenopause: A Review Progesteron in der Peri-und Postmenopause – ein Überblick Author P.-A. Regidor1, 2 Affiliations 1 Praxis für Frauenheilkunde, München 2 Velvian GmbH, Ismaning Key words l" hormone therapy l" progesterone l" menopause l" menopausal symptoms Schlüsselwörter l" Hormontherapie l" Progesteron l" Menopause l" Wechseljahresbeschwerden received 27. 1. 2014 revised 1. 10. 2014 accepted 1. 10. 2014

DOI http://dx.doi.org/ 10.1055/s-0034-1383297 Geburtsh Frauenheilk 2014; 74: 995–1002 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0016‑5751 Correspondence Pedro-Antonio Regidor, MD PhD Praxis für Frauenheilkunde Bauberger Straße 16 80992 München [email protected] 995 Regidor P-A. Progesterone in Peri- … Geburtsh Frauenheilk 2014; 74: 995 –1002 Review Deutschsprachige Zusatzinformationen online abrufbar unter: www.thieme-connect.de/ ejournals/toc/gebfra

! Investigations into the physiological effects of progesterone started at the beginning of the 20th century [1]. The destruction of the ovarian corpus luteum was found to result in abortion in pregnant animals. This could be prevented if animals were given an injection of corpus luteum extract. A number of research groups, working independently, finally managed to isolate pro- gesterone from corpus luteum extract in 1934. The substance was first known as progestin in the USA and as luteosterone in Europe. In 1935 scientists agreed to name it progesterone as an indication that this hormone plays in important role in preg- nancy ( pro gestationem [Latin]: i.e., favoring gestation) [2, 3]. In the mid-1940s, Russell Marker managed to synthesize large amounts of pure progesterone from diosgenin, which could be sourced from plants. However, very high oral doses were neces- sary to obtain biological effects. Advances in galenical formula- tion, particularly in micronization techniques, improved the re- sorption property of progesterone, and after 1980 oral therapy using natural progesterone was possible [4, 5]. Progesterone is a steroid with 21 carbon atoms. In the human body it is produced in syncytiotrophoblasts and luteinized gran- ulosa cells of the ovarian follicles, in the cortical fascicles and the retinal areas of the adrenal cortex. Precursors of progesterone include LDL, VLDL, HDL and choles- terol synthesized de novo (VDL: very low density lipoprotein). Around 95–98 % of progesterone in blood is protein-bound, with most of it bound to serum albumin. Oral administration increases plasma levels of progesterone metabolites, primarily of pregnan- diol, pregnanolone (dihydroprogesterone), pregnandione, 20- α- dihydroprogesterone and 17-OH-progesterone [6 –8]. 5- α-hy- droxysteroid dehydrogenase converts metabolic intermediates to allopregnanolone, an important neuroactive steroid [9, 10]. Progesterone has both systemic and local effects. At the systemic level, progesterone increases diuresis through activation of the renin-angiotensin system, triggers the catabolic metabolism, re- laxes smooth muscle cells, increases excretion of calcium and phosphorus, raises basal body temperature, has sedative and an- algesic effects, improves visual memory and the proliferation and differentiation of osteoblasts and has additionally been found to have an immunosuppressive effect [11]. For a long time, however, the established opinion was that oral administration of proges- terone had only limited efficacy, as its bioavailability was strongly reduced due to the hepatic first-pass effect [12]. This led to the use of synthetic gestagens such as derivatives of testos- terone or 17-hydroxyprogesterone, as they are more resistant to hepatic degradation. But synthetic gestagens are associated with significant side effects due to their anti- or pro-estrogen effects, anti- or pro-androgen effects, mineralocorticoid effects and neg- ative effects on glucose metabolism and lipid metabolism [13]. Advances in micronization and the suspension of progesterone in oil solutions has led to new data, which has demonstrated the bioavailability of orally administered progesterone [13]. Simon et al. additionally showed that the highest serum levels were ob- tained when oral progesterone preparations were taken together with food [14]. Progesterone effects a number of changes in the reproductive system and the mammary glands, which have important implica- tions for its potential therapeutic use. Effects include 1. transition of the endometrium from the proliferative to the se- cretory phase [15] 2. preparation of the endometrium for potential implantation [16, 17] 3. maintaining pregnancy [18] 4. the reduction of uterine muscular activity through the devel- opment of increased numbers of β-adrenergic receptors and the reduction of sensitivity to oxytocin [19 –21] 5. the reduction of prostaglandin synthesis [22] 6. stimulating the development of lobuli and mammary ducts in breast tissue [23, 24]. 7. High levels of progesterone during pregnancy serve to prepare the mammary glands for lactation [25]. These effects indicate a number of areas where progesterone ad- ministration could be beneficial. Indications for Progesterone Administration ! There are currently a number of well-known indications for pro- gesterone administration, both in gynecology and obstetrics. These include " primary or secondary amenorrhea [26] " infertility due to known corpus luteum insufficiency [27] " treatment of endometriosis [28, 29] " treatment of fibrocystic mastopathy [30] " treatment of premenstrual syndrome [31] " supporting the luteal phase during IVF treatment (IVF: in vitro fertilization) [32] " prevention of pregnancy loss [33] " protection of the endometrium during HT with estrogen [34 – 44] Several studies have recently shown that micronized progester- one is tolerated better than synthetic gestagens [35 –37]. Progesterone plays a very important role for the endometrium, primarily in the implantation and development of the fertilized ovum. It is significantly involved in the proliferative to secretory transition of the endometrium, the decidualization of the endo- metrium, in triggering the synthesis of PAPP ‑A (pregnancy-asso- ciated plasma protein A), PP14 (placental protein 14) and utero- globin, the development of PIBF (progesterone-induced blocking factor), the switch from Th1 to Th2 cells (Th cells: T helper cells), the stimulation of prostaglandin E2 production and suppression of the matrix metalloproteinases MMP3 and MMP9 [38]. All these factors are essential parts of normal development during pregnancy. In the breast, progesterone causes down-regulation of estrogen receptors and inhibits estrogen-induced proliferation of epithe- lial cells [39]. After initial stimulation progesterone can arrest hu- man cancer cell growth in the late G1 phase (G: gap) of the 2nd cycle [40]. In a study using breast tissue obtained by fine-needle aspiration biopsy it was found that normal increases in proges- terone during the luteal phase results in down-regulation of es- trogen receptors but not of progesterone receptors. This points to an important anti-estrogen and anti-proliferative effect in salen Beschwerden dar, bei gleichzeitig besserem Nutzen-Risiko- Profil als die synthetischen Gestagene. 996 Regidor P-A. Progesterone in Peri- … Geburtsh Frauenheilk 2014; 74: 995 –1002 GebFra Science breast epithelial cells [41]. Other studies have confirmed that cell proliferation depends directly on the estrogen-progesterone ra- tio in breast tissue and is lower in the luteal phase than in the fol- licular phase [42]. This means that progesterone exerts an overall protective effect on breast tissue. Additional factors which rein- force this protective effect include an apoptosis-inducing effect together with the inhibition of 17 β‑HSD (hydroxysteroid dehy- drogenase) reductive activity in breast tissue, which is particu- larly active in breast cancers [43, 44]. Progesterone in Peri- and Postmenopause ! Various effects of progesterone administration in peri- and post- menopause are summarized below. Effects on the endometrium Although the oral bioavailability of progesterone is not high, the PEPI trial convincingly demonstrated that progesterone offers endometrial protection in women receiving estrogens to treat menopausal symptoms. This placebo-controlled trial investi- gated the efficacy of micronized progesterone for the prevention of endometrial hyperplasia and compared a placebo group with 2 different MPA administration regimens (MPA: medroxyproges- terone acetate). Micronized progesterone, administered once daily for 12 days prior to going to bed was found to protect the endometrium from hyperplastic changes associated with estro- gen-only therapy as effectively as the two MPA therapies [34] (l " Table 1). Similar data on endometrial protection were present- ed previously by Lalumiere and colleagues [45]. They also showed that women who received micronized progesterone had significantly fewer bleeding episodes and shorter bleeding than the control group who received MPA. In this study the patients also received 200 mg progesterone for 12 days in every cycle. In a 2001 study of 336 women with early menopause, Pélissier et al. [46] also found that micronized progesterone provided effec- tive endometrial protection. In their study, one group received transdermal estrogen plus chlormadinone acetate 10 mg/day and the other group received transdermal estrogen plus 200 mg progesterone for 14 days. Around one third of the women who received micronized progesterone had amenorrhea after 6 and 18 months. Overall bleeding status was more stable with proges- terone than with chlormadinone acetate ( l " Fig. 1). As the transformation dose for progesterone is 2000 mg per cycle, patients should receive either 100 mg/day continuously or 200 mg/day sequentially for a period of 12 –14 days every cycle to ensure satisfactory secretory transformation of the endometri- um in women previously treated with estrogens [47]. Effect on the breast Since the publication of the WHI study [48] HT in menopause has been associated with increased rates of breast cancer. Both the data of the WHI study and the results of the Million Women Study [49] led at the beginning of 2000 to an abrupt drop in hor- mone treatments for menopausal symptoms. The association was also reported for animal experiments [50]: long-term administration of estradiol and progesterone had a promotional effect on breast cancer after treatment with carcino- genic substances or spontaneously. Investigations of breast cancer cell lines showed that high con- centrations of progesterone had an antiproliferative (pro-apo- ptotic) effect, but that the reverse effect was obtained with low MPA concentrations. Synthetic gestagens such as MPA or nor- ethisterone alone or in combination with estrogens can stimulate breast cancer cells in vitro. However, progesterone alone or in combination with estrogens had an antiproliferative or neutral effect [51 –53]. In a quantitative mouse model, Otto et al. [54] showed that the same dose of MPA had a proliferative effect on breast tissue and an inhibitory effect on the uterus, while no such association was found for progesterone. A twofold higher dose of progesterone was required to induce proliferative effects in breast tissue compared to the doses which resulted in complete inhibition of estradiol-activated endometrial proliferation. It ap- pears therefore that progesterone administration is associated with a beneficial safety margin between the desirable inhibition Table 1 Results of the endometrial biopsies at the end of the trial [34].

Placebo CEE alone CEE + cyclic MPA CEE + cont. MPA CEE + micronized progesterone Normal 116 45 112 119 114 Simple (cystic) hyperplasia 1 33 4 1 5 Complex (adenomatous) hyperplasia 1 27 2 0 0 Atypical hyperplasia 0 14 0 0 1 Adenocarcinoma 1 0 0 0 0 CEE: conjugated equine estrogens; MPA: medroxyprogesterone acetate; cont.: continuous Percentage with complete amenorrhea CMA – 6 months Percent 40 35 30 25 20 15 10 5 0 CMA – 18 months Progesterone – 6 months Progesterone – 18 months Fig. 1 Amenorrhea after 6 and 18 months receiving either 10 mg chlor- madinone acetate or 200 mg progesterone administered cyclically for 14 days [46]. CMA: chlormadinone acetate. 997 Regidor P-A. Progesterone in Peri- … Geburtsh Frauenheilk 2014; 74: 995 –1002 Review of endometrial proliferation and undesirable epithelial cell prolif- eration in the mammary gland. No such safety margin was found for MPA. Murkes et al. [55] reported that treating postmenopau- sal women with 1.5 mg/day estradiol in the form of a gel and 200 mg progesterone administered orally for 14/28 days did not significantly increase epithelial cell proliferation in the breast compared to baseline values, while the administration of 0.625 mg/day CEE (conjugated equine estrogen) plus 5 mg MPA on 14 out of 28 days significantly increased proliferation. At the same time, the number of bcl-2-positive (bcl-2: B-cell lymphoma 2) breast cells was reduced, indicating an apoptotic effect at the end of the gestagen phase. In recent years, the importance of mammographic density as a risk factor for the development of breast cancer has become in- creasingly clear [56]. In a case-control study, Heusinger et al. [57] showed that patients with breast cancer had a significantly higher mammographic density compared to women without dis- ease. However, both the female breast and mammographic den- sity is affected by many hormonal influences. Boyd et al. [58] showed that mammographic density increases with HT, while antiestrogen tamoxifen treatment decreases mammographic density. The impact of HT has also been confirmed by other study groups [59–61]. Tolerability and Safety of Progesterone ! As shown in l" Table 2, progesterone is associated with a number of partial side effects which clearly differentiate it from all syn- thetic gestagens. This profile outlines the individual effects on different parameters in the human body. Effect on glucose metabolism Several studies (PEPI, WHI and HERS trials [PEPI: Postmenopau- sal Estrogen/Progestin Interventions; HERS: Heart and Estrogen/ Progestin Replacement Study]) [34, 48, 62] have shown that non- diabetic postmenopausal women have significantly lower fasting blood glucose levels and even lower fasting insulin levels during oral estrogen or estrogen-gestagen treatment compared to placebo groups. The administration of progesterone is not ex- pected to cause any relevant changes to glucose metabolism. The E3N Study [63] also showed that administration of transder- mal estrogen with micronized progesterone significantly re- duced the risk for diabetes, even over a significant period of expo- sure. In contrast to synthetic gestagens progesterone has no de- trimental effect on glucose balance. Effect on blood pressure All existing studies on progesterone show that, in general, the ef- fect of progesterone on blood pressure is neutral and it may even have a slightly antihypertensive effect. The PEPI trial found no in- crease in blood pressure in either the estrogen group or the es- trogen/progesterone group compared to placebo-treated con- trols [64]. Progesterone and body weight Both the PEPI trial [64] and the WHI Study showed [34, 48] that postmenopausal HT-treated women had a lower body weight gain on average compared to women receiving no hormone ther- apy. The progesterone administered during the PEPI trial was also neutral with regard to body weight, suggesting that progesterone has no effect on this parameter. Table 2 Progesterone and synthetic gestagens and their properties (mod. nach [73]. Proges- togenic Anti- gonado- tropic Anti- estro- genic Estro- genic Andro- genic Anti- andro- genic Gluco- corticoid Antimineralo- corticoid Progesterone + + + –– ±++ Dydrogesterone + – + –– ± – ± Medrogestone + + + –– ± –– 17a-Hydroxyprogesterone derivatives Chlormadinone acetate + + + –– ++ – Cyproterone acetate + + + –– ++ + – Megestrol acetate + + + – ±+ + – Medroxyprogesterone acetate + + + – ± – + – 19-Nor-progesterone derivatives Nomegestrol acetate + + + –– ± –– Promegestone + + + – – ––– Trimegestone + + + –– ± – ± 19-Nortestosterone derivatives Norethisterone + + + + + ––– Lynestrenol + + + + + ––– Norethynodrel ± + + + + ––– Levonorgestrel + + + – + ––– Norgestimate + + + – + ––– Desogestrel + + + – + ––– Gestoden + + + – + – ++ Dienogest + + ± ± – + –– Spirolonactone derivatives Drospirenone + + + –– + – + 998 Regidor P-A. Progesterone in Peri- … Geburtsh Frauenheilk 2014; 74: 995 –1002 GebFra Science Progesterone and Lipid Metabolism ! Overall, estrogen therapy is associated with positive long-term effects (HDL ‑C levels [C: cholesterol] increase, LDL ‑C levels de- crease) on the lipoprotein profile of postmenopausal women, although it should be noted that this effect was found more com- monly for orally administered estrogen. In contrast to these findings, synthetic gestagens if combined with estrogens reduce HDL ‑C concentrations. A direct compari- son with synthetic gestagens (MPA, norethisterone or norgestrel) showed that micronized progesterone has fewer negative effects on HDL ‑C metabolites compared to synthetic gestagens. Saari- koski et al. [65] carried out a study in 80 perimenopausal women treated for functional menometrorrhagia. The women were di- vided into 2 groups to receive either 300 mg/day oral micronized progesterone for 10 days per cycle or 15 mg/day norethisterone for 10 days per cycle over 6 consecutive cycles. The study showed that HDL ‑C levels remained stable with progesterone, but there was marked decrease in HDL‑C levels in the norethisterone group (p < 0.001). The previously mentioned PEPI trial also showed that, in significant contrast to medroxyprogesterone used in the other arms of the study, progesterone has the least impact on the pos- itive effect on HDL ‑C caused by estrogens [64] ( l " Fig. 2). Progesterone and the CNS Progesterone exerts several effects on the central nervous sys- tem. Chief among these are a sedative effect, created by its me- tabolites, in particular 5 α-a n d5 β-allopregnanolone. Doses of up to 1200 mg have been trialed in various studies. It was found that patients subjectively described a feeling of fatigue but expe- rienced no impairment of psychological or physical performance [66–68]. This phenomenon can be put to good use to treat post- menopausal women suffering from sleep disorders by adminis- tering progesterone in the evening. Here again an important dif- ference was noted between progesterone and the synthetic ges- tagens: synthetic gestagens are not converted into the above- mentioned metabolites and thus have no soporific effect. Schu- macher et al. [69] reported that progesterone has neuroactive properties and can exert anxiolytic and antiepileptic effects in se- lected patients [70, 71]. Safety of progesterone in hormone therapy The previously mentioned PEPI trial [34] was the first big study to use oral micronized progesterone to treat postmenopausal symptoms. In this 3-year, placebo-controlled prospective study, 875 non-hysterectomized postmenopausal women were ran- domized and divided into the following study arms: placebo for 28 days, 0.625 mg CEE/day for 28 days, 0.625 mg CEE plus 2.5 mg medroxyprogesterone acetate either continuously or cyclically for the first 12 days, and 0.625 mg CEE plus 200 mg progesterone HDL levels with different gestagens and progesterone (PEPI Study) 0 0.5 1 1.5 Years 22 . 53 mg/dl 6 5 4 3 2 1 0 –1 –2 CEE + MPA (cont.) CEE + MPA (cyclical) CEE + proges- terone CEE alone Placebo Fig. 2 Changes in HDL ‑C levels (HDL‑C: lipoproteins with high density cholesterol) after estrogen monotherapy, estrogen and progesterone ad- ministration, cyclical administration of estrogen with MPA (medroxypro- gesterone acetate), continuous administration of estrogen with MPA, and placebo (from the PEPI trial) [64]. CEE: conjugated equine estrogen. Relative risk (RR) for breast cancer

of the E3N Study (n = 80377): Breast cancer RR according to HRT type

group = non-receivers (RR =1) Oral estrogens with… Transdermal estrogen with… Norethisterone acetate (46) Cyproterone acetate (34) MPA (29) Promegestone (13) Progesterone (121) Dydrogesterone (90) Nomegestrol acetate (91) Promegestone (69) Chlormadinone acetate (35) Medrogestone (28) 1 1.5 2 2.5 3 3.5 2,1 2,6 1,5 1,6 1,1 1,2 1,6 1,5 1,5 2,0 Heterogeneity NS Heterogeneity NS Heterogeneity NS

according to HRT type (n = 2354 women) Fig. 3 Breast cancer rates: results of the E3N Study [63]. MPA: Medroxyprogesterone acetate. 999 Regidor P-A. Progesterone in Peri- … Geburtsh Frauenheilk 2014; 74: 995 –1002 Review for the first 12 days. Endometrial biopsies were performed in 596 patients after the therapy to demonstrate the endometrial safety of HT. As expected, the rate of endometrial changes was highest in the group which had received CEE alone, while no significant endometrial pathologies were found in patients in the 3 study arms treated according to gestagen protocols ( l " Table 1 ). The study investigated many additional parameters including subjec- tive well-being, metabolic parameters, blood pressure, changes in body weight, etc. No negative effects were found in the group of women receiving progesterone. A much bigger study, the French E3N cohort study [63], collected data from more than 87 000 postmenopausal women to assess the efficacy and safety with a particular focus on breast cancer and thromboembolism rates. A number of different gestagens were compared with micronized progesterone. Breast cancer rates and thromboembolism rates did not increase after the administration of progesterone in HT in contrast to women who did not receive hormone treatment (odds ratio was 1.08 for breast cancer [l " Fig. 3] and 0.9 for thrombosis [ l" Fig. 4]). The most recent publication of the KEEPS Reports (KEEPS: Kro- nos Early Estrogen Prevention Study) in 2011 not only reported positive effects of progesterone on cognitive functions but also described a protective effect for the cardiovascular system; at the same time, the risk of breast cancer was not increased in women receiving either placebo or 0.45 mg CEE plus 200 mg pro- gesterone for 12 days or 50 µg estradiol per day administered via a patch together with 200 mg progesterone for 12 days. Rates for endometrial cancer, stroke, myocardial infarction and thrombo- embolism were also the same in all 3 groups [72]. The only absolute contraindications for progesterone administra- tion in the narrower sense are rare autoimmune allergic reac- tions and anti-epileptic drugs or tuberculostatic agents as the in- take of these drugs is associated with rapid hepatic degradation.

! Progesterone or corpus luteum hormone can be used safely and effectively to treat menopausal symptoms or for hormone substi- tution in menopausal women, as it constitutes a bio-identical preparation which can be used to correct deficiency symptoms. Administration to achieve the necessary transformation dose for endometrial safety through progesterone can be either continu- ous (100 mg/day) or cyclical (200 mg/day) for 12 –14 days. Conflict of Interest ! The author is medical director of the company Velvian GmbH, a member of the Exeltis Group.

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