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Differential effects of progestins on the brain
Maturitas 46S1 (2003) S71–S75
Differential effects of progestins on the brain Christian J. Gruber∗ , Johannes C. Huber Department of Gynecological Endocrinology and Reproductive Medicine, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Abstract Interactions exist between progestins and the ␥-aminobutyric acid (GABA) receptor subtype A where C21 -steroids function as activators. Other interactions between progesterone and neurotransmitter systems include stimulation of dopamine release in striatal tissue, stimulation of GnRH release from hypothalamic neurons and inhibition of opioid receptor binding and activation. Cyproterone acetate increases dopaminergic responses and binds to opiate receptors independently of its classical effect on the androgen receptor. Progesterone substitution in perimenopausal women promotes length and quality of sleep. This effect seems most prominent for progesterone administered vaginally. Progestins also play a role in the pathogenesis of migraine. Migraine symptoms occur predominantly during the perimenstrual stage. Women who suffer from menstrual migraine triggered by premenstrual progesterone loss often benefit from cyclic progesterone administration. This may be because progesterone and allopregnenolone reduce meningeal release of substance P and inhibit the development of neurogenic oedema. Women whose migraine symptoms subside during pregnancy, however, benefit from intramuscular medroxyprogesterone acetate. Progesterone, generated from pregnenolone by Schwann cells, also enhances myelin synthesis. Myelination of axons is promoted when progesterone is added to cultures of rat dorsal root ganglia. No reliable data exist with respect to the effects of other progestins on demyelinating disease. Progestins promote the growth of meningioma as progesterone receptors predominate in meningioma tissue. Progesterone and synthetic progestins should therefore not be prescribed in these patients. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Progestins; Progesterone receptors; Brain
1. Introduction Gonadal steroid research has traditionally been very much focused on estrogens. The C21 -steroids were seemingly attributed a lower priority, although knowledge about their widespread molecular actions was mounting. Clinical research with respect to progestins concentrated primarily on endometrial ∗ Corresponding author. Tel.: +43-1-40400/2816; fax: +43-1-40400/2817. E-mail address: christian [email protected] (C.J. Gruber).
protection and bleeding patterns, neglecting the role of progesterone-specific menopausal symptoms such as sleep alterations, depression and water retention. Likewise, clinical trials investigating the extragonadal effects of the different progestins are rare and the field of progestins remains relatively open. The Women’s Health Initiative Trial [1] however, as an example of current interest, demonstrated diverging results between the estrogen plus progestin group and the estrogen only group of post-menopausal women, hence indicating a more complex role of progestins in the female body than was previously assumed. This
0378-5122/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2003.09.021
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C.J. Gruber, J.C. Huber / Maturitas 46S1 (2003) S71–S75
review will focus on the effects of progesterone and other progestins on the central nervous system and neuronal tissues.
2. Interaction of progestins with neurotransmitter systems Epidemiological investigations have shown that the prescription rate for psychopharmalogical drugs rises dramatically in the female in the perimenopausal period [2]. The explanation for this phenomenon cannot only be due to specific life events occurring at that time, such as the so-called ‘empty-nest syndrome’. Endocrine changes with respect to progesterone production influence women’s psychosocial behaviour in the perimenopause and profound interactions exist between progesterone and its metabolites and the ␥-aminobutyric acid (GABA) receptor subtype A [3]. Activation of the GABA-A receptor makes the cell membrane permeable to chloride ions and produces strong sedating effects. Apart from the physiological ligand, barbiturates and benzodiazepines utilize this receptor. C21 -steroids are also capable of occupying the GABA-A receptor molecule to induce GABA-specific reactions. In mice, complete anaesthesia can be induced by administration of progesterone [4] and, in progesterone-rich pregnant women, 30–50% less barbiturates [5] are required for abdominal surgery as compared with non-gravid women. Additionally, progesterone has a modulatory influence on sleep intensity and pattern [6] and after progesterone ingestion fatigue can occur as a side effect. Interestingly, the GABA receptor displays a high level of plasticity during the menstrual cycle [7], allowing adaptation of the GABA-system to different endocrine situations. The progesterone metabolite predominately active at GABA receptors is 3␣-hydroxy-5␣-pregnan-20-one, which can be generated by the glial cells [8] of the central nervous system. It is known from clinical experience that progesterone substitution in perimenopausal women may help to promote length and quality of sleep. This effect seems most prominent for progesterone administered vaginally. Although less pronounced with the pregnanes, such as oral medroxyprogesterone acetate, or the gonanes, such as oral lynestrenol, every medication package of these synthetic progestins
is accompanied by a warning not to use these steroids prior to driving a car since fatigue can occur. Interaction of progesterone with the GABA-A receptor also confers anticonvulsive properties on this steroid. Women with polycystic ovaries often develop luteal phase deficits with insufficient progesterone production. These women have a higher incidence of unilateral focal epilepsy [9] and progesterone substitution ameliorates this form of convulsion in some, although not all, cases [10]. No data, however, exist with respect to other progestins in this context. In summary, therefore, progesterone has anxiolytic, hypnotic and anticonvulsant properties. Other interactions between progesterone and neurotransmitter systems include stimulation of dopamine release in striatal tissue [11], stimulation of GnRH release from hypothalamic neurons [12] and inhibition of opioid receptor binding and activation [13]. Animal studies have suggested that the latter function has major implications in female reproductive behaviour. Progestins are currently used in a wide range of therapeutic indications. The pathogenesis of the premenstrual syndrome, although complex and until now only partly understood, seems to involve dysfunction in several neurotransmitter systems that are also known to be influenced by progesterone or its metabolites. In severe cases, drugs with neuropharmacological effects, such as anxiolytics and antidepressants, are indicated. Treating the psychological symptoms of premenstrual syndrome (premenstrual dysphoric disorder) with progestins has yielded conflicting results so far. Whereas most synthetic progestins have consistently failed to ameliorate this syndrome in clinical trials, there are a few trials using natural progesterone applied intravaginally or orally in micronized form that have yielded beneficial effects. Not surprisingly, the application of natural progesterone ameliorated specifically the symptoms of anxiety, tension and irritability [14,15]. Dydrogesterone is also often used to treat premenstrual symptoms and it offers a well tolerated alternative for women who object to the vaginal route of administration of natural progesterone. Cyproterone acetate is a potent progestin with partial androgen antagonistic activity. It has been shown to ameliorate post-menopausal psychological symptoms and to increase the dopaminergic response, as assessed using the prolactin response to the dopamine-blocking agent sulpiride [16]. This progestogen also profoundly
C.J. Gruber, J.C. Huber / Maturitas 46S1 (2003) S71–S75
alters aggressive behaviour in humans and animals. Self-injurious behaviour, for instance, is decreased by cyproterone acetate in adult male rhesus monkeys [17]. This may be explained by the anti-androgenic activity of cyproterone acetate that suppresses the hypothalamic gonadal axis and decreases testosterone. In addition, this progestin may reduce levels of 5-hydroxy indole acetic acid (5-HIAA) and homo vanillic acid (HVA), metabolites of serotonin and dopamine. Therefore, the reduction in auto-aggressive behaviour may also be related to an increase in the availability of active monoamines in the central nervous system. Interestingly, and in accordance with these findings, psychiatrists have recently started to evaluate the potential benefits of cyproterone acetate in the treatment of Tourette’s syndrome. Drugs acting on androgen receptors modify opioid transmission in the central nervous system. In a study conducted in mice, the binding of opioid [3 H]-diprenorphine to mouse brain membranes was modified by cyproterone acetate. Of the various progestins examined, only cyproterone acetate inhibited [3 H]-diprenorphine binding without modifying its association rate. These results suggest that cyproterone acetate binds to opiate receptors independently of its classical intracellular androgenic receptor effect [18].
3. Progestins and multiple sclerosis Multiple sclerosis, a demyelinating disease, is more common in women than in men and is most frequent between the ages of 30 and 40 years [19]. Pregnancy ameliorates the symptoms of this disease temporarily, whereas an exacerbation is often noted in the post-partum period. These observations have indicated that sex steroids may play a role in the pathogenesis of this disease. Progesterone particularly seems to have a partially protective effect in multiple sclerosis. It suppresses the immune system in a similar, but less pronounced, manner to that of cortisone and it also has anti-inflammatory effects [20]. These are mediated by inhibition of the ubiquitous inflammation transmitter nuclear factor kappa B. In experimental allergic encephalomyelitis, an in vitro model for multiple sclerosis, histological changes typical of this disease were less pronounced after progesterone administration. Progesterone, generated from pregnenolone by
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Schwann cells, enhances myelin synthesis by inducing the expression of neural signals that are important for myelin synthesis. After cryo-lesion, for example, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impairs remyelination of the axon. In contrast, administration of progesterone or its precursor, pregnenolone, to the lesion site increases the extent of myelin sheath formation. Myelination of axons can also be promoted when progesterone is added to cultures of rat dorsal root ganglia [21]. No reliable data exist with repect to the effects of other progestins on demyelinating disease.
4. Progesterone and meningioma Meningioma are hormone-sensitive tumours of the central nervous system. They occur more frequently in women than in men, and an association between this type of brain tumour and pregnancy is well established [22]. During the course of pregnancy, an exacerbation in growth and size of the tumors is often observed, whereas partial tumour regression is sometimes evident post-partum [23]. An association between meningioma and hormone-sensitive breast cancer is also recognised [24]. Surgery is the most important step in the treatment procedure and is often inevitable. However, surgical intervention is impossible in some cases and endocrinological intervention offers a therapeutical option for those unlucky patients. Unlike breast cancer tissue, progesterone receptor predominance has been observed in meningioma tissues [25]. Although the connection between progesterone receptor status and surgical outcome is not fully understood, the presence of this steroid receptor is thought to be a positive prognostic factor. Recent investigations support previous studies showing an association between low or absent expression of progesterone receptors and a higher risk of recurrence [26]. Long-term therapy with an antiprogesterone is generally well tolerated; reported sideeffects include breast tenderness, fatigue, exanthema and loss of libido. Mifepristone requires further clinical evaluation in this context, but it has already been shown to have helped a number of patients affected by inoperable meningioma [27, 28]. Progesterone and synthetic progestins, such as medroxyprogesterone
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acetate, lynestrenol or norethisterone acetate, should not be prescribed in these patients.
5. Progesterone and migraine Migraine headache in women most commonly occurs during the reproductive period of life and subsides after the menopause. Changes in cerebral vessel wall characteristics, such as increased rigidity, account for this age-related phenomenon, but an endocrinological influence is also evident. In affected women, migraine symptoms appear to occur predominantly during the menstrual and premenstrual stages [29] and fluctuating female sex hormones function as migraine triggers in this scenario. Headache activity during the luteal and premenstrual phases seems to be related to luteal phase progesterone levels. At the same time, menstrual migraine is greatest if oestradiol levels are high, if the oestradiol/progesterone ratio is high, and if headache activity is increased. Alternatively, pregnancy often ameliorates migraine episodes and reduces their frequency, the causative factor most likely being the absence of periodic hormonal fluctuations. These two different endocrine situations, menstrual cycle and gestation, yield two therapeutic possibilities for female migraine patients [30]. Women who suffer from menstrual migraine triggered by premenstrual progesterone loss often benefit from cyclic progesterone administration. This may be related to the progesterone and allopregnenolone effect of lowering meningeal release of substance P and inhibiting the development of neurogenic oedema, as shown in animal studies [31]. Vaginal administration of micronized progesterone is recommended in this setting, as synthetic oral progestins have been reported to worsen migraine headache in a number of studies. Women whose migraine symptoms subside during pregnancy, however, benefit from intramuscular administration of medroxyprogesterone acetate. This intervention balances sex steroid fluctuations and minimises endocrine oscillations for a longer period of time.
6. Conclusion A precise history taken from post-menopausal women will often reveal progesterone-specific
complaints. These, and the modulatory effects of progestins in connection with multiple sclerosis and certain subtypes of epilepsy, indicate a potent role for the C21 -steroids in neuronal tissues. As to the effects of different progestins on the central nervous system, the major neuroactive steroid seems to be progesterone and its metabolites itself. Little information on the differential effects of synthetic progestins on the central nervous system is currently available. Although closer examinations are warranted in the future, progestins must now be regarded as equally multifunctional as estrogens.
References [1] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33. [2] Sator MO, Wieser F, Gruber DM, Joura EA, Huber JC. Trends in the prescription of psychotropic drugs and hormone substitutes in Austria. Wien Klin Wochenschr 1999;111(10): 402–5. [3] Genazzani AR, Stomati M, Morittu A, Bernardi F, Monteleone P, Casarosa E, et al. Progesterone, progestagens and the central nervous system. Hum Reprod 2000;15(Suppl 1):14– 27. [4] Hogskilde S, Nielsen JW, Carl P, Sorensen MB. Pregnanolone emulsion. A new steroid preparation for intravenous anaesthesia: an experimental study in mice. Anaesthesia 1987;42 (6):586–90. [5] Backstrom T, Gee KW, Lan N, Sorensen M, Wahlstrom G. Steroids in relation to epilepsy and anaesthesia. Ciba Found Symp 1990;153:225–30, discussion 230-9. [6] Lancel M, Faulhaber J, Holsboer F, Rupprecht R. The GABA(A) receptor antagonist picrotoxin attenuates most sleep changes induced by progesterone. Psychopharmacology (Berl) 1999;141(2):213–9. [7] Concas A, Follesa P, Barbaccia ML, Purdy RH, Biggio G. Physiological modulation of GABA(A) receptor plasticity by progesterone metabolites. Eur J Pharmacol 1999;375(1– 3):225–35. [8] Garcia-Segura LM, Chowen JA, Naftolin F. Endocrine glia: roles of glial cells in the brain actions of steroid and thyroid hormones and in the regulation of hormone secretion. Front Neuroendocrinol 1996;17(2):180–211. [9] Herzog AG. Polycystic ovarian syndrome in women with epilepsy: epileptic or iatrogenic? Ann Neurol 1996;39(5):559– 60. [10] Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 1999;52(9):1917–8.
C.J. Gruber, J.C. Huber / Maturitas 46S1 (2003) S71–S75 [11] Petitclerc M, Bedard PJ, Di Paolo T. Progesterone releases dopamine in male and female rat striatum: a behavioral and microdialysis study. Prog Neuropsychopharmacol Biol Psychiatry 1995;19(3):491–7. [12] Cho BN, Seong JY, Cho H, Kim K. Progesterone stimulates GnRH gene expression in the hypothalamus of ovariectomized, estrogen treated adult rats. Brain Res 1994;652 (1):177–80. [13] Sinchak K, Micevych PE. Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior. J Neurosci 2001;21(15):5723–9. [14] Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA, Burrows GD. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br Med J (Clin Res Ed) 1985;290(6482):1617–21. [15] Baker ER, Best RG, Manfredi RL, Demers LM, Wolf GC. Efficacy of progesterone vaginal suppositories in alleviation of nervous symptoms in patients with premenstrual syndrome. J Assist Reprod Genet 1995;2(3):205–9. [16] Paoletti AM, Floris S, Mannias M, Orru M, Crippa D, Orlandi R, et al. Evidence that cyproterone acetate improves psychological symptoms and enhances the activity of the dopaminergic system in post-menopause. J Clin Endocrinol Metab 2001;86(2):608–12. [17] Eaton GG, Worlein JM, Kelley ST, Vijayaraghavan S, Hess DL, Axthelm MK, et al. Self-injurious behavior is decreased by cyproterone acetate in adult male rhesus (Macaca mulatta). Horm Behav 1999;35(2):195–203. [18] Gutierrez M, Menendez L, Ruiz-Gayo M, Hidalgo A, Baamonde A. Cyproterone acetate displaces opiate binding in mouse brain. Eur J Pharmacol 1997;328(1):99–102. [19] Giesser BS. Gender issues in multiple sclerosis. Neurology 2002;8(6):351–6. [20] Kalkhoven E, Wissink S, van der Saag PT, van der Burg B. Negative interaction between the RelA(p65) subunit of NFkappaB and the progesterone receptor. J Biol Chem 1996; 271(11):6217–24. [21] Koenig HL, Schumacher M, Ferzaz B, Thi AN, Ressouches A, Guennoun R, et al. Progesterone synthesis and myelin
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formation by Schwann cells. Science 1995;268(5216):1500– 3. Bondy M, Ligon BL. Epidemiology and etiology of intracranial meningiomas: a review. J Neurooncol 1996;29(3):197– 205. Isla A, Alvarez F, Gonzalez A, Garcia-Grande A, PerezAlvarez M, Garcia-Blazquez M. Brain tumor and pregnancy. Obstet Gynecol 1997;89(1):19–23. Bonito D, Giarelli L, Falconieri G, Bonifacio-Gori D, Tomasic G, Vielh P. Association of breast cancer and meningioma. Report of 12 new cases and review of the literature. Pathol Res Pract 1993;189(4):399–404. Carroll RS, Glowacka D, Dashner K, Black PM. Progesterone receptor expression in meningiomas. Cancer Res 1993;53(6):1312–6. Strik HM, Strobelt I, Pietsch-Breitfeld B, Iglesias-Rozas JR, Will B, Meyermann R. The impact of progesterone receptor expression on relapse in the long-term clinical course of 93 benign meningiomas. In Vivo 2002;16(4):265–70. Matsuda Y, Kawamoto K, Kiya K, Kurisu K, Sugiyama K, Uozumi T. Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo. J Neurosurg 1994; 80(3):527–34. Haak HR, de Keizer RJ, Hagenouw-Taal JC, van Seters AP, Vielvoye GJ, van Dulken H. Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 1990; 336(8707):124–5. Beckham JC, Krug LM, Penzien DB, Johnson CA, Mosley TH, Meeks GR, et al. The relationship of ovarian steroids, headache activity and menstrual distress: a pilot study with female migraineurs. Headache 1992;32(6): 292–7. MacGregor A. Migraine associated with menstruation. Funct Neurol 2000;15(Suppl 3):143–53. Limmroth V, Lee WS, Moskowitz MA. GABAA-receptormediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges. Br J Pharmacol 1996;117(1):99– 104.
Differential effects of progestins on the brain Christian J. Gruber∗ , Johannes C. Huber Department of Gynecological Endocrinology and Reproductive Medicine, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Abstract Interactions exist between progestins and the ␥-aminobutyric acid (GABA) receptor subtype A where C21 -steroids function as activators. Other interactions between progesterone and neurotransmitter systems include stimulation of dopamine release in striatal tissue, stimulation of GnRH release from hypothalamic neurons and inhibition of opioid receptor binding and activation. Cyproterone acetate increases dopaminergic responses and binds to opiate receptors independently of its classical effect on the androgen receptor. Progesterone substitution in perimenopausal women promotes length and quality of sleep. This effect seems most prominent for progesterone administered vaginally. Progestins also play a role in the pathogenesis of migraine. Migraine symptoms occur predominantly during the perimenstrual stage. Women who suffer from menstrual migraine triggered by premenstrual progesterone loss often benefit from cyclic progesterone administration. This may be because progesterone and allopregnenolone reduce meningeal release of substance P and inhibit the development of neurogenic oedema. Women whose migraine symptoms subside during pregnancy, however, benefit from intramuscular medroxyprogesterone acetate. Progesterone, generated from pregnenolone by Schwann cells, also enhances myelin synthesis. Myelination of axons is promoted when progesterone is added to cultures of rat dorsal root ganglia. No reliable data exist with respect to the effects of other progestins on demyelinating disease. Progestins promote the growth of meningioma as progesterone receptors predominate in meningioma tissue. Progesterone and synthetic progestins should therefore not be prescribed in these patients. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Progestins; Progesterone receptors; Brain
1. Introduction Gonadal steroid research has traditionally been very much focused on estrogens. The C21 -steroids were seemingly attributed a lower priority, although knowledge about their widespread molecular actions was mounting. Clinical research with respect to progestins concentrated primarily on endometrial ∗ Corresponding author. Tel.: +43-1-40400/2816; fax: +43-1-40400/2817. E-mail address: christian [email protected] (C.J. Gruber).
protection and bleeding patterns, neglecting the role of progesterone-specific menopausal symptoms such as sleep alterations, depression and water retention. Likewise, clinical trials investigating the extragonadal effects of the different progestins are rare and the field of progestins remains relatively open. The Women’s Health Initiative Trial [1] however, as an example of current interest, demonstrated diverging results between the estrogen plus progestin group and the estrogen only group of post-menopausal women, hence indicating a more complex role of progestins in the female body than was previously assumed. This
0378-5122/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2003.09.021
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review will focus on the effects of progesterone and other progestins on the central nervous system and neuronal tissues.
2. Interaction of progestins with neurotransmitter systems Epidemiological investigations have shown that the prescription rate for psychopharmalogical drugs rises dramatically in the female in the perimenopausal period [2]. The explanation for this phenomenon cannot only be due to specific life events occurring at that time, such as the so-called ‘empty-nest syndrome’. Endocrine changes with respect to progesterone production influence women’s psychosocial behaviour in the perimenopause and profound interactions exist between progesterone and its metabolites and the ␥-aminobutyric acid (GABA) receptor subtype A [3]. Activation of the GABA-A receptor makes the cell membrane permeable to chloride ions and produces strong sedating effects. Apart from the physiological ligand, barbiturates and benzodiazepines utilize this receptor. C21 -steroids are also capable of occupying the GABA-A receptor molecule to induce GABA-specific reactions. In mice, complete anaesthesia can be induced by administration of progesterone [4] and, in progesterone-rich pregnant women, 30–50% less barbiturates [5] are required for abdominal surgery as compared with non-gravid women. Additionally, progesterone has a modulatory influence on sleep intensity and pattern [6] and after progesterone ingestion fatigue can occur as a side effect. Interestingly, the GABA receptor displays a high level of plasticity during the menstrual cycle [7], allowing adaptation of the GABA-system to different endocrine situations. The progesterone metabolite predominately active at GABA receptors is 3␣-hydroxy-5␣-pregnan-20-one, which can be generated by the glial cells [8] of the central nervous system. It is known from clinical experience that progesterone substitution in perimenopausal women may help to promote length and quality of sleep. This effect seems most prominent for progesterone administered vaginally. Although less pronounced with the pregnanes, such as oral medroxyprogesterone acetate, or the gonanes, such as oral lynestrenol, every medication package of these synthetic progestins
is accompanied by a warning not to use these steroids prior to driving a car since fatigue can occur. Interaction of progesterone with the GABA-A receptor also confers anticonvulsive properties on this steroid. Women with polycystic ovaries often develop luteal phase deficits with insufficient progesterone production. These women have a higher incidence of unilateral focal epilepsy [9] and progesterone substitution ameliorates this form of convulsion in some, although not all, cases [10]. No data, however, exist with respect to other progestins in this context. In summary, therefore, progesterone has anxiolytic, hypnotic and anticonvulsant properties. Other interactions between progesterone and neurotransmitter systems include stimulation of dopamine release in striatal tissue [11], stimulation of GnRH release from hypothalamic neurons [12] and inhibition of opioid receptor binding and activation [13]. Animal studies have suggested that the latter function has major implications in female reproductive behaviour. Progestins are currently used in a wide range of therapeutic indications. The pathogenesis of the premenstrual syndrome, although complex and until now only partly understood, seems to involve dysfunction in several neurotransmitter systems that are also known to be influenced by progesterone or its metabolites. In severe cases, drugs with neuropharmacological effects, such as anxiolytics and antidepressants, are indicated. Treating the psychological symptoms of premenstrual syndrome (premenstrual dysphoric disorder) with progestins has yielded conflicting results so far. Whereas most synthetic progestins have consistently failed to ameliorate this syndrome in clinical trials, there are a few trials using natural progesterone applied intravaginally or orally in micronized form that have yielded beneficial effects. Not surprisingly, the application of natural progesterone ameliorated specifically the symptoms of anxiety, tension and irritability [14,15]. Dydrogesterone is also often used to treat premenstrual symptoms and it offers a well tolerated alternative for women who object to the vaginal route of administration of natural progesterone. Cyproterone acetate is a potent progestin with partial androgen antagonistic activity. It has been shown to ameliorate post-menopausal psychological symptoms and to increase the dopaminergic response, as assessed using the prolactin response to the dopamine-blocking agent sulpiride [16]. This progestogen also profoundly
C.J. Gruber, J.C. Huber / Maturitas 46S1 (2003) S71–S75
alters aggressive behaviour in humans and animals. Self-injurious behaviour, for instance, is decreased by cyproterone acetate in adult male rhesus monkeys [17]. This may be explained by the anti-androgenic activity of cyproterone acetate that suppresses the hypothalamic gonadal axis and decreases testosterone. In addition, this progestin may reduce levels of 5-hydroxy indole acetic acid (5-HIAA) and homo vanillic acid (HVA), metabolites of serotonin and dopamine. Therefore, the reduction in auto-aggressive behaviour may also be related to an increase in the availability of active monoamines in the central nervous system. Interestingly, and in accordance with these findings, psychiatrists have recently started to evaluate the potential benefits of cyproterone acetate in the treatment of Tourette’s syndrome. Drugs acting on androgen receptors modify opioid transmission in the central nervous system. In a study conducted in mice, the binding of opioid [3 H]-diprenorphine to mouse brain membranes was modified by cyproterone acetate. Of the various progestins examined, only cyproterone acetate inhibited [3 H]-diprenorphine binding without modifying its association rate. These results suggest that cyproterone acetate binds to opiate receptors independently of its classical intracellular androgenic receptor effect [18].
3. Progestins and multiple sclerosis Multiple sclerosis, a demyelinating disease, is more common in women than in men and is most frequent between the ages of 30 and 40 years [19]. Pregnancy ameliorates the symptoms of this disease temporarily, whereas an exacerbation is often noted in the post-partum period. These observations have indicated that sex steroids may play a role in the pathogenesis of this disease. Progesterone particularly seems to have a partially protective effect in multiple sclerosis. It suppresses the immune system in a similar, but less pronounced, manner to that of cortisone and it also has anti-inflammatory effects [20]. These are mediated by inhibition of the ubiquitous inflammation transmitter nuclear factor kappa B. In experimental allergic encephalomyelitis, an in vitro model for multiple sclerosis, histological changes typical of this disease were less pronounced after progesterone administration. Progesterone, generated from pregnenolone by
S73
Schwann cells, enhances myelin synthesis by inducing the expression of neural signals that are important for myelin synthesis. After cryo-lesion, for example, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impairs remyelination of the axon. In contrast, administration of progesterone or its precursor, pregnenolone, to the lesion site increases the extent of myelin sheath formation. Myelination of axons can also be promoted when progesterone is added to cultures of rat dorsal root ganglia [21]. No reliable data exist with repect to the effects of other progestins on demyelinating disease.
4. Progesterone and meningioma Meningioma are hormone-sensitive tumours of the central nervous system. They occur more frequently in women than in men, and an association between this type of brain tumour and pregnancy is well established [22]. During the course of pregnancy, an exacerbation in growth and size of the tumors is often observed, whereas partial tumour regression is sometimes evident post-partum [23]. An association between meningioma and hormone-sensitive breast cancer is also recognised [24]. Surgery is the most important step in the treatment procedure and is often inevitable. However, surgical intervention is impossible in some cases and endocrinological intervention offers a therapeutical option for those unlucky patients. Unlike breast cancer tissue, progesterone receptor predominance has been observed in meningioma tissues [25]. Although the connection between progesterone receptor status and surgical outcome is not fully understood, the presence of this steroid receptor is thought to be a positive prognostic factor. Recent investigations support previous studies showing an association between low or absent expression of progesterone receptors and a higher risk of recurrence [26]. Long-term therapy with an antiprogesterone is generally well tolerated; reported sideeffects include breast tenderness, fatigue, exanthema and loss of libido. Mifepristone requires further clinical evaluation in this context, but it has already been shown to have helped a number of patients affected by inoperable meningioma [27, 28]. Progesterone and synthetic progestins, such as medroxyprogesterone
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acetate, lynestrenol or norethisterone acetate, should not be prescribed in these patients.
5. Progesterone and migraine Migraine headache in women most commonly occurs during the reproductive period of life and subsides after the menopause. Changes in cerebral vessel wall characteristics, such as increased rigidity, account for this age-related phenomenon, but an endocrinological influence is also evident. In affected women, migraine symptoms appear to occur predominantly during the menstrual and premenstrual stages [29] and fluctuating female sex hormones function as migraine triggers in this scenario. Headache activity during the luteal and premenstrual phases seems to be related to luteal phase progesterone levels. At the same time, menstrual migraine is greatest if oestradiol levels are high, if the oestradiol/progesterone ratio is high, and if headache activity is increased. Alternatively, pregnancy often ameliorates migraine episodes and reduces their frequency, the causative factor most likely being the absence of periodic hormonal fluctuations. These two different endocrine situations, menstrual cycle and gestation, yield two therapeutic possibilities for female migraine patients [30]. Women who suffer from menstrual migraine triggered by premenstrual progesterone loss often benefit from cyclic progesterone administration. This may be related to the progesterone and allopregnenolone effect of lowering meningeal release of substance P and inhibiting the development of neurogenic oedema, as shown in animal studies [31]. Vaginal administration of micronized progesterone is recommended in this setting, as synthetic oral progestins have been reported to worsen migraine headache in a number of studies. Women whose migraine symptoms subside during pregnancy, however, benefit from intramuscular administration of medroxyprogesterone acetate. This intervention balances sex steroid fluctuations and minimises endocrine oscillations for a longer period of time.
6. Conclusion A precise history taken from post-menopausal women will often reveal progesterone-specific
complaints. These, and the modulatory effects of progestins in connection with multiple sclerosis and certain subtypes of epilepsy, indicate a potent role for the C21 -steroids in neuronal tissues. As to the effects of different progestins on the central nervous system, the major neuroactive steroid seems to be progesterone and its metabolites itself. Little information on the differential effects of synthetic progestins on the central nervous system is currently available. Although closer examinations are warranted in the future, progestins must now be regarded as equally multifunctional as estrogens.
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