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Progesterone is a steroid hormone that is essential for the regulation of reproductive function. Progesterone has been approved for several indications including the treatment of anovulatory menstrual cycles, assisted reproductive technology, contraception during lactation and, when combined with estrogen, for the prevention of endometrial hyperplasia in postmenopausal hormonal therapy. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system. This physiological hormone is poorly absorbed when administered in a crystalline form and is not active when given orally, unless in micronized form, or from different non-oral delivery systems that allow a more constant delivery rate. A limited number of preclinical studies have been conducted to document the toxicity, carcinogenicity and overall animal safety of progesterone delivered from different formulations, and these rather old studies showed no safety concern. More recently, it has been shown in animal experiments that progesterone, its metabolite allopregnanolone and structurally related progestins have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. These recent preclinical findings have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

Progesterone shows anti-inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Because neurosteroids have been implicated as protective factors for MS and EAE, we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR) and aromatase, whereas changes of 3β-hydroxysteroid dehydrogenase (3β-HSD) were not significant. mRNA translocator protein (18 kDa) (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNAs. Progesterone pretreatment before EAE induction increased Star, VDAC, P450scc, 5α-reductase type I, 3α-HSOR and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNAs. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3β-HSD, 3α-HSOR and 5α-reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS. The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti-inflammatory effects of exogenous progesterone given to EAE mice., (© 2017 British Society for Neuroendocrinology.)

Multiple Sclerosis affects mainly women and consists in intermittent or chronic damages to the myelin sheaths, focal inflammation, and axonal degeneration. Current therapies are limited to immunomodulators and antiinflammatory drugs, but there is no efficient treatment for stimulating the endogenous capacity of myelin repair. Progesterone and synthetic progestins have been shown in animal models of demyelination to attenuate myelin loss, reduce clinical symptoms severity, modulate inflammatory responses and partially reverse the age-dependent decline in remyelination. Moreover, progesterone has been demonstrated to promote myelin formation in organotypic cultures of cerebellar slices. In the present study, we show that progesterone and the synthetic 19-nor-progesterone derivative Nestorone® promote the repair of severe chronic demyelinating lesions induced by feeding cuprizone to female mice for up to 12 weeks. Progesterone and Nestorone increase the density of NG2(+) oligodendrocyte progenitor cells and CA II(+) mature oligodendrocytes and enhance the formation of myelin basic protein (MBP)- and proteolipid protein (PLP)-immunoreactive myelin. However, while demyelination in response to cuprizone was less marked in corpus callosum than in cerebral cortex, remyelination appeared earlier in the former. The remyelinating effect of progesterone was progesterone receptor (PR)-dependent, as it was absent in PR-knockout mice. Progesterone and Nestorone also decreased (but did not suppress) neuroinflammatory responses, specifically astrocyte and microglial cell activation. Therefore, some progestogens are promising therapeutic candidates for promoting the regeneration of myelin., (© 2014 Wiley Periodicals, Inc.)

Progesterone is commonly considered as a female reproductive hormone and is well-known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of γ-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The 2012 London Summit on Family Planning called for innovative solutions for increasing contraceptive access for 120 million women and girls by 2020. One way of contributing to this goal is to address the contraceptive needs of postpartum women, who have considerable unmet need especially during lactation. The progesterone vaginal ring (PVR) has been shown to be effective and safe for breastfeeding women and has the potential to enhance contraceptive choice. This user-controlled method reduces dependence on health care providers and has the potential to reduce some access-related barriers that users face. Postpartum women who have used the method have found it easy to use and find it acceptable. A well-designed introductory approach is important to ensure that the PVR is integrated into health systems., Conclusion: The PVR is a new technology that increases contraceptive options for breastfeeding women and has the potential to improve the health of women and their infants. Careful planning with attention paid to numerous factors can result in its successful introduction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Progesterone is a steroid hormone that is essential for the regulation of reproductive function. The main physiological roles of this hormone have been widely described. Progesterone and progestins have been approved for a number of indications including the treatment of irregular and anovulatory menstrual cycles and, when combined with estrogen, for contraception, and the prevention of endometrial hyperplasia in postmenopausal hormonal replacement therapy (HRT) regimens. Lack of understanding between the differences in categories of the progestins as well as with the physiological hormone has resulted in considerable controversy surrounding the use of progestins for HRT regimens. Newer evidence suggests that there are distinct differences between the molecules and there is no progestin class effect, with regard to benefits or side-effects. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system and the vessels. Recently, it has been shown in animal experiments that progesterone and the progestin Nestorone(®) have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. The potential benefits of natural progesterone and its related derivatives warrant further investigation. It is hoped that a better understanding of the mechanism of action of progesterone and selected progestins will help in defining better therapies for men and women.

Enhancing the endogenous capacity of myelin repair is a major therapeutic challenge in demyelinating diseases such as multiple sclerosis. We found that progesterone and the synthetic 19-norprogesterone derivative 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione (Nestorone) promote the remyelination of axons by oligodendrocytes after lysolecithin-induced demyelination in organotypic cultures of cerebellar slices taken from postnatal rats or mice. The intracellular progesterone receptors (PR) mediate the proremyelinating actions of Nestorone, because they are not observed in slices from PR knockout mice. Notably, Nestorone was less efficient in heterozygous mice, expressing reduced levels of PR, suggesting PR haploinsufficiency in myelin repair. Using mice expressing the enhanced green fluorescent protein (EGFP) under the control of the proteolipid gene promoter, we showed that both progesterone and Nestorone strongly increased the reappearance of cells of the oligodendroglial lineage in the demyelinated slices. In contrast to Nestorone, the pregnane derivative medroxyprogesterone acetate had no effect. The increase in oligodendroglial cells by Nestorone resulted from enhanced NG2(+) and Olig2(+) oligodendrocyte progenitor cell (OPC) recruitment. In cocultures of lysolecithin-demyelinated cerebellar slices from wild-type mice apposed to brain stem slices of proteolipid gene promoter-EGFP mice, Nestorone stimulated the migration of OPC towards demyelinated axons. In this coculture paradigm, Nestorone indeed markedly increased the number of EGFP(+) cells migrating into the demyelinated cerebellar slices. Our results show that Nestorone stimulates the recruitment and maturation of OPC, two steps which are limiting for efficient myelin repair. They may thus open new perspectives for the use of progestins, which selectively target PR, to promote the endogenous regeneration of myelin.

The progesterone vaginal ring (PVR) has been shown to be effective as a contraceptive in breastfeeding women who need a better method of spacing pregnancies, and previous clinical trials of 1-year duration demonstrated its efficacy to be similar to that of the IUD during lactation. The duration of lactational amenorrhea is significantly prolonged in PVR users in comparison to IUD users with fewer median numbers of bleeding/spotting (B/S) episodes and B/S days. This long-acting delivery system designed for 3-month use needs to be renewed every 3 months as long as breastfeeding continues. The system designed as a matrix ring delivers 10 mg/day of the physiological hormone progesterone. Various factors such as comfort, ease of use, user control, rather than provider-dependent, and the fact that it contains a natural hormone have contributed to a high acceptability of the PVR method by breastfeeding women. The frequency of breastfeeding, breast milk volume and infant growth were not different in PVR users or IUD users, and the safety of this new method has been well documented. This article describes the available information and the results of the studies that led to approval of this method in several countries in Latin America so far. Further evaluation of the PVR acceptability in different populations where breastfeeding is popular and highly recommended for the infant's benefit is warranted., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Aim: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women., Method: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium., Results: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group., Conclusion: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

New options for hormonal replacement therapy (HRT) include non-oral, low-dose sustained delivery of progestins in different formulations. Since the Women's Health Initiative (WHI) study, prescription trends were observed selecting progesterone over other progestins, or delivering the progestin parenterally, in order to reach low systemic levels of the steroid. Such modalities include progesterone vaginal rings or gels, and intra-uterine systems (IUSs). When given via the transdermal and intranasal routes, the hormones are delivered systemically although the first liver impact is by-passed. Of the progestins selected for delivery of low doses by means of an IUS, or transdermally, only very active molecules can be used. An IUS approved for HRT in several countries delivers very low doses of levonorgestrel (LNG) in the uterine cavity. Nestorone is well absorbed transdermally from a gel as well as from a metered dose transdermal system (MTDS) that sprays an invisible film on the skin. Transdermal patches combining oestradiol with either norethisterone acetate or LNG have been available for several years. Although parenteral administration of progesterone or low-dose progestins should in theory be associated with fewer side-effects than oral therapy, the long-term safety of the newer systems warrants further evaluation.

Progesterone, known for its role in pregnancy, also exerts marked effects on the nervous system. Its neuroprotective and promyelinating actions, now well documented by experimental studies, make it a particularly promising therapeutic agent for neuroinjury and neurodegenerative diseases. This concept has recently been translated into clinical practice, though there is need for more experimental studies and investigations on the mechanisms of the actions of progesterone. However, it is important to be aware that most of the experimental research concerns the effects of physiological progesterone. Although progesterone represents an interesting therapeutic option, the recognition of its beneficial effects on the nervous system also suggests novel therapeutic benefits for some synthetic progestins derived from progesterone, currently used for contraception or in postmenopausal hormone replacement therapies (HRTs).

Background: Limited information is available on the effects of progestins on breast cancer progression and metastasis. Cell migration and invasion are central for these processes, and require dynamic cytoskeletal and cell membrane rearrangements for cell motility to be enacted., Methods: We investigated the effects of progesterone (P), medroxyprogesterone acetate (MPA), drospirenone (DRSP) and nestorone (NES) alone or with 17beta-estradiol (E2) on T47-D breast cancer cell migration and invasion and we linked some of these actions to the regulation of the actin-regulatory protein, moesin and to cytoskeletal remodeling., Results: Breast cancer cell horizontal migration and invasion of three-dimensional matrices are enhanced by all the progestins, but differences are found in terms of potency, with MPA being the most effective and DRSP being the least. This is related to the differential ability of the progestins to activate the actin-binding protein moesin, leading to distinct effects on actin cytoskeleton remodeling and on the formation of cell membrane structures that mediate cell movement. E2 also induces actin remodeling through moesin activation. However, the addition of some progestins partially offsets the action of estradiol on cell migration and invasion of breast cancer cells., Conclusion: These results imply that P, MPA, DRSP and NES alone or in combination with E2 enhance the ability of breast cancer cells to move in the surrounding environment. However, these progestins show different potencies and to some extent use distinct intracellular intermediates to drive moesin activation and actin remodeling. These findings support the concept that each progestin acts differently on breast cancer cells, which may have relevant clinical implications.

Since the publication of the Women's Health Initiative (WHI) study followed by the results of the Million Women Study (MWS), the role of hormonal therapy in postmenopausal women has been further challenged. The risks attributed to hormone therapy have been overestimated and the data has been wrongly extrapolated to the whole class of therapies. The trends in postmenopausal hormonal therapy seem now to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus, based on the assumption that a lesser stimulation of the liver proteins and a neutral metabolic profile would be more favorable in terms of cardiovascular and venous risk. The combination of non-oral administration of estradiol and local delivery of progesterone or a progestin such as levonorgestrel by means of gels, sprays, vaginal rings or intrauterine systems would represent new methods of replacement therapy for the menopausal woman, improving compliance and minimizing the risks of hormone replacement. Several of these systems are either available or in development. Long-term studies on the risk/benefit of various non-oral formulations are certainly warranted.

The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies.

Therapeutic Applications: Antiprogestins are a promising class of therapeutic agents in the field of reproductive health. Mifepristone (exRU486) remains the leading compound of this class and is the only one presently used in clinical practice. Beyond the main action of antiprogestins on human pregnancy, these compounds may prove useful in the treatment of uterine leiomyomas and endometriosis, and for contraception. IN CANCEROLOGY: Rare tumors such as meningiomas or leiomyoarcomas expressing progesterone receptors may be successfully treated with these antihormones. MAIN INDICATIONS: The main characteristics of the different antiprogestins discovered so far are addressed and the key results from the large clinical studies conducted with mifepristone are described here for indications where the product is approved for clinical use: medical termination of pregnancy during the first trimester, cervical dilatation prior to surgical termination of pregnancy, preparation for prostaglandin action in the therapeutic termination of pregnancy beyond the first trimester, labor induction in case of foetal death in utero.

Percutaneous progesterone topically applied on the breast has been proposed and widely used in the relief of mastalgia and benign breast disease by numerous gynecologists and general practitioners. However, its chronic use has never been evaluated in relation to breast cancer risk. The association between percutaneous progesterone use and the risk of breast cancer was evaluated in a cohort study of 1150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person-years. Percutaneous progesterone had been prescribed to 58% of the women. There was no association between breast cancer risk and the use of percutaneous progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. Taken together, these results suggest at least an absence of deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

One hundred eighty-four patients with benign breast disease (BBD) were studied and compared with 50 normal women. All of the women had ovulatory cycles according to a biphasic basal body temperature and a plasma prolactin in the normal range. Their corpus luteum function was evaluated by way of plasma progesterone (P) and estradiol (E2) determinations at days 5, 7, and 9 of the hyperthermic phase. In the 184 patients, plasma P over plasma E2 ratio during the luteal phase was found significantly lower than in normal women. When the patients were grouped according to type of breast lesions, it appeared that plasma P was constantly lower in all groups than in the normal women, while plasma E2 was either normal or elevated in the groups of patients with adenosis tumors and increased nodularity of both breasts. From these results it may be postulated that an imbalance in the secretion of E2 and P by the corpus luteum is a constant finding in women with benign breast disease.

Estimations of estradiol, progesteron and other biochemical analyses support the hypothesis of a relative unopposed hyperestrogenism as cause of benign breast diseases. Additional factors are insufficient luteal phases combined with hyperprolactinemia or transient prolactin pulses. Progestagen treatment applied either topically or both orally and topically can correct the imbalance and perhaps prevent breast cancer.

The results of exploration of the corpus luteum in 125 patients with benign breast disease are analysed. In 109 patients, plasma oestradiol and progesterone were measured at various times during the hyperthermic phase of the menstrual cycle. The results obtained were compared with those obtained in normal women explored during the same phase of the cycle. The average daily values for plasma progesterone obtained in this group of 109 patients was significantly lower than that found in the normal women, whilst there was no change in oestradiol levels. In addition, 16 patients were studied daily throughout the period of hyperthermia. In 8 cases, there the hyperoestrogenism, with or without progesterone insifficiency of the corpus luteum. In all, secretory imbalance of the corpus luteum with a tendency to relative or absolute hyperoestrogenism was a constant finding in women with benign breast disease.

Progesterone (P), the natural hormone, binds to its specific receptors to induce specific progestational effects. In addition to this binding, P is able to interfere with the binding sites of other steroids. Therefore the natural hormone exhibits an anti-estrogenic activity, and anti-androgenic activity and also exerts anti-mineralocorticoid effects. For a long time progesterone could not be used in clinical applications because of a rapid liver inactivation after oral administration. An oral micronized preparation of progesterone is now available which produces adequate plasma and tissue levels of progesterone. The preparation reproduces the anti-estrogenic effect of the natural hormone on the endometrium at the dose of 200 mg daily. It also reproduces the anti-mineralocorticoid effect and has no androgenic action. No side effects have been reported as far as lipids profile, coagulation factors and blood pressure are concerned. Therefore oral micronized progesterone appears suitable for hormonal replacement therapy in various areas, essentially postmenopause therapy, premenstrual syndrome, correction of irregular cycles and pregnancy maintenance.

Following the publication of the Women's Health Initiative study, the controversy was raised regarding the role of progestins in hormonal replacement therapy (HRT). Some of the most prescribed molecules, with partial androgenic or glucocorticoid activity, have been shown to oppose partially the beneficial effect of estrogens on surrogate markers of cardiovascular disease risk. Unfortunately, this concern has been directed towards progestins as a class effect, although striking differences exist among the types of molecules used. The synthetic progestins used in HRT have varying pharmacologic properties depending on the molecules from which they are derived, either testosterone or progesterone. Very small structural changes in these molecules may induce considerable difference in their effects on various targets and especially on the surrogate markers of cardiovascular disease risk, where some molecules may reverse the beneficial effects of estrogen. Natural progesterone and some of its derivatives such as the 19-norprogesterone molecules or the new molecules drospirenone, a potent antimineralocorticoid agent with a beneficial effect on blood pressure, and dienogest do not exert any androgenic effect and have no negative effect on the lipids or on the endothelial cells. Although it is likely that the new progestins may be neutral on the coronary disease risk, when administered to the younger postmenopausal woman, this has not as yet been documented by large, randomized, controlled trials. [ABSTRACT FROM AUTHOR]

Following the publication of the Women's Health Initiative study, the controversy was raised regarding the role of progestins in hormonal replacement therapy (HRT). Some of the most prescribed molecules, with partial androgenic or glucocorticoid activity, have been shown to oppose partially the beneficial effect of estrogens on surrogate markers of cardiovascular disease risk. Unfortunately, this concern has been directed towards progestins as a class effect, although striking differences exist among the types of molecules used. The synthetic progestins used in HRT have varying pharmacologic properties depending on the molecules from which they are derived, either testosterone or progesterone. Very small structural changes in these molecules may induce considerable difference in their effects on various targets and especially on the surrogate markers of cardiovascular disease risk, where some molecules may reverse the beneficial effects of estrogen. Natural progesterone and some of its derivatives such as the 19-norprogesterone molecules or the new molecules drospirenone, a potent antimineralocorticoid agent with a beneficial effect on blood pressure, and dienogest do not exert any androgenic effect and have no negative effect on the lipids or on the endothelial cells. Although it is likely that the new progestins may be neutral on the coronary disease risk, when administered to the younger postmenopausal woman, this has not as yet been documented by large, randomized, controlled trials. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to evaluate the potential action of Nestorone (alone or in combination with estradiol valerate) on the level of allopregnanolone and of the opioid β-endorphin in selected brain areas. Wistar ovariectomized rats were given 0.05mg/(kgday) of estradiol valerate (E2V) or subcutaneous Nestorone at three dose levels: low dose (10μg/(kgday)), antiovulatory dose (50μg/(kgday)) and high dose (250μg/(kgday)) with and without E2V. E2V therapy reversed the reduction of allopregnanolone and β-endorphin induced by ovariectomy anywhere was analyzed except for the adrenal gland. Nestorone showed no effect on allopregnanolone concentration in serum or any part of the brain tissue when given alone while it had a synergistic increasing effect in allopregnanolone concentration in some parts of the brain (hippocampus, hypothalamus, anterior pituitary and serum) when given at high dose of 250μg/(kgday) in combination with E2V. At lower doses it possesses a synergistic effect with E2V only in the hippocampus (at 50μg/(kgday)) and in the anterior pituitary (at 10 and 50μg/(kgday)). Nestorone administered alone at any dose led to significant increase in β-endorphin levels in the hippocampus only while, in the high dose group, there was a significant increase in endorphin levels in anterior pituitary and hypothalamus in addition to hippocampus as compared to ovariectomized control rats. In addition, only the highest dose of Nestorone added to estrogen increased β-endorphin levels of hippocampus and plasma. Thus the lower doses of Nestorone alone or in combination with estrogen do not seem to exert any great effect on both allopregnanolone and β-endorphin. It is only the highest dose of Nestorone that increases allopregnanolone and β-endorphin levels in selected brain areas, which are the hippocampus, the hypothalamus, the anterior pituitary and serum/plasma. This suggests that Nestorone at the antiovulatory dose levels may not alter the positive effects of estrogen treatment on mood and behaviour. [Copyright &y& Elsevier]