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Actions of Progesterone

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The Actions of Progesterone

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In women, progesterone is a steroid hormone produced primarily by the ovaries and adrenal glands. Progesterone has a direct affect on the function of the reproductive system, the nervous system, the cardiovascular system and the skeletal system.

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Blood sugar levels, skin and other tissues and functions are also significantly influenced by progesterone.

Like all steroid hormones, excessive amounts of progesterone can contribute to a number of increased health risks.

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Though proper progesterone levels are critical for the prevention of endometrial hyperplasia

and endometrial cancer, the actions of this hormone extend far beyond endometrial health. Therefore it is crucial that proper levels also be maintained in women who have had a hysterectomy.

Following is a list of some of the actions and functions of progesterone. More information and references can be found in the book What's Your Menopause Type?

The Menstrual Cycle and the Endometrium

Progesterone prevents development of endometrial cancer 1. Low progesterone with unopposed estrogen may be one cause of dysfunctional uterine bleeding 2. Progesterone may help decrease uterine contractions, cramping and pain 3, 4.

 

The Vagina & Urinary Tract

Excessive progesterone may increase urinary incontinence and even counteract the beneficial effects of estrogen in maintaining urinary control 5, 6, 7, 8.

 

The Libido

Excessive progesterone may decrease libido due to antiestrogen and anti-androgen effect 9, 10. As well as decreasing libido, excessive levels may induce depression 11.

 

Blood Sugar & Insulin

While estrogens help the cells of the body utilize glucose more efficiently by making them more sensitive to insulin, progesterone can cause a decrease in insulin sensitivity, having an effect on blood sugar that is similar glucocorticosteroids 12. This interference with the action of insulin can interfere with normal glucose uptake and cause insulin resistance 13, 14, 15, 16, 17.

The ability of progesterone to interfere with proper function of insulin and glucose has since been associated with gestational diabetes 18, 19, 20 as well as hormone replacement therapies 21,15, 22, 12 and has been been observed in both synthetic & non-synthetic progesterone 20, 23, 24, 12. Even the high progesterone levels which occur naturally during the luteal phase can induce insulin resistance in some women 21, 16.

 

The Brain Mood & Memory

 

Progesterone and its metabolites result in increased relaxation and reduced anxiety in a way that is similar to the effects of benzodiazepines 25, 26 by a direct effect on neurotransmitter receptors called Gamma-AminoButyric Acid type A (GABAA) receptors 27. When progesterone levels drop a woman can experience withdrawals similar to the withdrawal seen with benzodiazepine, barbiturate, and alcohol withdrawal 29.

Excessive levels may cause decreased coordination, slowed reflexes, depression and impaired memory and reasoning skills 30, 31, 32, 33, 34. The sedating effects of excessive progesterone can cause drowsiness and even induce sleep 35, 32, 36. The nerve calming effect of progesterone is so pronounced that both natural progesterone and medroxyprogesterone have both been shown to decrease seizures in women with epilepsy 37, 38.

Progesterone has a protective, stimulating effect on breathing patterns during sleep, resulting in decreased incidence of sleep apnea, a serious condition in which the body is deprived of oxygen 39, 40, 41, 42.

The action of progesterone on GABAA receptors have been associated with an increase appetite and food intake 43, 44, 45.

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The Breasts

Progesterone insufficiency may play a role in the development of breast cancer 46, however progesterone may also play a role in the proliferation of some progesterone receptor forms of breast cancer 47. This increased risk is associated with the increased production of IGF-1 by breast cells stimulated by excessive progesterone 48, 49 - resulting in the proliferation of several forms of breast cancer cells 50.

 

The Skin

Though progesterone does not increase skin thickness 51, it does increase blood flow to the skin 52 resulting in an increased ability to sweat and loose the extra heat through the skin 53. Progesterone can also raise body temperature, enhancing the ability to tolerate cold 53.

 

Bones & Osteoporosis

Progesterone has stimulating effect on the bone building osteoblasts resulting in increased bone building activity 54, 55, 56, 57, 58, 59, 60. This is due to a direct stimulation of the progesterone receptors in osteoblast bone cells 61, 62, as well as an increased secretion of IGF-1 and other growth factors by the bone cells exposed to porgesterone 63, 64, 65. The most positive effect is seen when estrogen & progesterone are used in combination 66.

 

The Heart

Natural micronized progesterone may cause a significant lowering of in blood pressure in postmenopausal women with mildly to moderately high blood pressure 67, possibly due to the vasodilating effect of action of progesterone 68.

Natural micronized progesterone will not reduce the good HDL levels that are enhanced by estrogen replacement 69, and will result in higher HDL than when synthetic progestogens are used 70.

This lipoprotein (a) benefit of estrogen is not diminished by either synthetic (medroxyprogesterone acetate) or natural micronized progesterone 71, 72.

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References:

(1) Mauvais-Jarvis P, Kuttenn F. [Is progesterone insufficiency carcihogenic]? [Article in French] Nouv Presse Med 1975 Feb 1;4(5):323-326

(2) Gorodeski IG, Geier A, Siegal A, Beery R, Lunenfield B, Langzam J, Bahari CM. Decreased Ratio of TotalProgesteroen to Total Estradiol Receptor Levels in Endometria of Women with Adult Dysfunctional Uterine Bleeding. Gynecol. Obstet. Invest. 22:22-28 (1986)

(3) Putnam CD, Brann DW, Kolbeck RC, Mahesh VB. Inhibition of uterine contractility by progesterone and progesterone metabolites: mediation by progesterone and gamma amino butyric acidA receptor systems. Biol Reprod 1991 Aug;45(2):266-272

(4) Cabral R, Gutierrez M, Fernandez AI, Cantabrana B, Hidalgo A. Progesterone and pregnanolone derivatives relaxing effect on smooth muscle. Gen Pharmacol 1994 Jan;25(1):173-178

(5) Batra SC, Iosif CS. Progesterone receptors in the female lower urinary tract. J Urol 1987 Nov;138(5):1301-4

(6) Caissel J, Ghaddar Y. [Urodynamic study of urinary incontinence appearing in the fifth month of pregnancy and persisting after delivery. The role of progesterone].[Article in French] Ann Urol (Paris) 1984 Sep;18(5):356-60

(7) Rud T. The effects of estrogens and gestagens on the urethral pressure profile in urinary continent and stress incontinent women. Acta Obstet Gynecol Scand 1980;59(3):265-70

(8) Miodrag A, Castleden CM, Vallance TR. Sex hormones and the female urinary tract. Drugs 1988 Oct;36(4):491-504

(9) Mauvais-Jarvis P, Kuttenn F. [Is progesterone insufficiency carcihogenic]? [Article in French] Nouv Presse Med 1975 Feb 1;4(5):323-326

(10) Amadeo M. Antiandrogen treatment of aggressivity in men suffering from dementia. J Geriatr Psychiatry Neurol 1996 Jul;9(3):142-5

(11) Glick ID, Bennett SE. Psychiatric complications of progesterone and oral contraceptives. J Clin Psychopharmacol 1981 Nov;1(6):350-367

(12) Lindheim SR, Presser SC, Ditkoff EC, Vijod MA, Stanczyk FZ, Lobo RA. A possible bimodal effect of estrogen on insulin sensitivity in postmenopausal women and the attenuating effect of added progestin. Fertil Steril 1993 Oct;60(4):664-7

(13) Sutter-Dub MT, Dazey B. [Role of progesterone in the insulin-resistance during pregnancy in the rat].[Article in French] Ann Endocrinol (Paris) 1979 Jan-Feb;40(1):37-8

(14) Sutter-Dub MT. Effects of pregnancy and progesterone and/or oestradiol on the insulin secretion and pancreatic insulin content in the perfused rat pancreas. Diabete Metab 1979 Mar;5(1):47-56

(15) Elkind -Hirsch KE, Sherman LD, Malinak R. Hormone replacement therapy alters insulin sensitivity in young women with premature ovarian failure. J Clin Endocrinol Metab 1993 Feb;76(2):472-5

(16) Tsibris JC, Raynor LO, Buhi WC, Buggie J, Spellacy WN. Insulin receptors in circulating erythrocytes and monocytes from women on oral contraceptives or pregnant women near term. J Clin Endocrinol Metab 1980 Oct;51(4):711-7

(17) Leturque A, Satabin P, Ferre P, Girard J. [Insulin resistance during pregnancy].

[Article in French] Ann Endocrinol (Paris) 1980 Nov-Dec;41(6):573-8

(18) Ri K. [Study on insulin resistance in rats treated with estrogen and progesterone--assessment with the euglycemic glucose clamp technic].[Article in Japanese] Nippon Naibunpi Gakkai Zasshi 1987 Jun 20;63(6):798-808

(19) Sutter-Dub MT, Dazey B, Vergnaud MT, Madec AM. Progesterone and insulin-resistance in the pregnant rat. I. In vivo and in vitro studies. Diabete Metab 1981 Jun;7(2):97-104

(20) Sutter-Dub MT, Vergnaud MT. Progesterone and insulin resistance. III. Time-course study of progesterone action on differentially labelled 14C-glucose utilization by adipose tissue and isolated adipocytes of the female rat. J Physiol (Paris) 1981 Sep;77(6-7):797-802

(21) Puah JA, Bailey CJ. Effect of ovarian hormones on glucose metabolism in mouse soleus muscle. Endocrinology 1985 Oct;117(4):1336-40

(22) Colacurci N, Zarcone R, Mollo A, Russo G, Passaro M, de Seta L, de Franciscis P. Effects of hormone replacement therapy on glucose metabolism. Panminerva Med 1998 Mar;40(1):18-21

(23) Colacurci N, Zarcone R, Mollo A, Russo G, Passaro M, de Seta L, de Franciscis P. Effects of hormone replacement therapy on glucose metabolism. Panminerva Med 1998 Mar;40(1):18-21

(24) Kumagai S, Holmang A, Bjorntorp P. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand 1993 Sep;149(1):91-7

(25) Lancel M, Faulhaber J, Holsboer F, Rupprecht R. Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators. Am J Physiol 1996 Oct;271(4 Pt 1):E763-E772

(26 Putnam CD, Brann DW, Kolbeck RC, Mahesh VB. Inhibition of uterine contractility by progesterone and progesterone metabolites: mediation by progesterone and gamma amino butyric acidA receptor systems. Biol Reprod 1991 Aug;45(2):266-272

(27) Backstrom T. Symptoms related to the menopause and sex steroid treatments. Ciba Found Symp 1995;191:171-180

(29) Smith SS, Gong QH, Li X, Moran MH, Bitran D, Frye CA, Hsu FC. Withdrawal from 3alpha-OH-5alpha-pregnan-20-One using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety. J Neurosci 1998 Jul 15;18(14):5275-84

(30) Freeman EW, Purdy RH, Coutifaris C, Rickels K, Paul SM. Anxiolytic metabolites of progesterone: correlation with mood and performance measures following oral progesterone administration to healthy female volunteers. Neuroendocrinology 1993 Oct;58(4):478-484

(31) Rice MM, Graves AB, McCurry SM, Larson EB. Estrogen replacement therapy and cognitive function in postmenopausal women without dementia. Am J Med 1997 Sep 22;103(3A):26S-35S

(32) Freeman EW, Weinstock L, Rickels K, Sondheimer SJ, Coutifaris C. A placebo-controlled study of effects of oral progesterone on performance and mood. Br J Clin Pharmacol 1992 Mar;33(3):293-298

(33) Korneyev A, Costa E. Allopregnanolone (THP) mediates anesthetic effects of progesterone in rat brain. Horm Behav 1996 Mar;30(1):37-43

(34) Glick ID, Bennett SE. Psychiatric complications of progesterone and oral contraceptives. J Clin Psychopharmacol 1981 Nov;1(6):350-367

(35) Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol 1988 Nov;159(5):1203-1209

(36) de Wit H, Rukstalis M. Acute effects of triazolam in women: relationships with progesterone, estradiol and allopregnanolone. Psychopharmacology (Berl) 1997 Mar;130(1):69-78

(37) Herzog AG. Reproductive endocrine considerations and hormonal therapy for women with epilepsy. Epilepsia 1991;32 Suppl 6:S27-33

(38) Galli R, Michelini S, Bartalena L, Massetani R, Pani L, Grasso L, Cassano GB, Martino E, Purdy RH, Murri L. Circulating levels of anticonvulsant metabolites of progesterone in women with partial epilepsy in the intercritical phase. Ital J Neurol Sci 1996 Aug;17(4):277-281.

(39) Block AJ, Wynne JW, Boysen PG. Sleep-disordered breathing and nocturnal oxygen

desaturation in postmenopausal women. Am J Med 1980 Jul;69(1):75-79

(40) Bayliss DA, Millhorn DE, Gallman EA, Cidlowski JA. Progesterone stimulates respiration through a central nervous system steroid receptor-mediated mechanism in cat. Proc Natl Acad Sci U S A 1987 Nov;84(21):7788-92

(41) Pickett CK, Regensteiner JG, Woodard WD, Hagerman DD, Weil JV, Moore LG. Progestin and estrogen reduce sleep-disordered breathing in postmenopausal women. J Appl Physiol 1989 Apr;66(4):1656-61

(42) Bayliss DA, Cidlowski JA, Millhorn DE. The stimulation of respiration by progesterone in ovariectomized cat is mediated by an estrogen-dependent hypothalamic mechanism requiring gene expression. Endocrinology 1990 Jan;126(1):519-27

(43) Fieldstone A, Zipf WB, Sarter MF, Berntson GG. Food intake in Prader-Willi syndrome and controls with obesity after administration of a benzodiazepine receptor agonist. Obes Res 1998 Jan;6(1):29-33

(44) Lett BT, Grant VL, Neville LL, Davis MJ, Koh MT Chlordiazepoxide counteracts activity-induced suppression of eating in rats. Exp Clin Psychopharmacol 1997 Feb;5(1):24-7

(45) Chen SW, Rodriguez L, Davies MF, Loew GH. The hyperphagic effect of 3 alpha-hydroxylated pregnane steroids in male rats. Pharmacol Biochem Behav 1996 Apr;53(4):777-782

(46) Mauvais-Jarvis P, Kuttenn F. [Is progesterone insufficiency carcihogenic]? [Article in French] Nouv Presse Med 1975 Feb 1;4(5):323-326

(47) Umekita Y, Yoshida H. Immunohistochemical study of hormone receptor and hormone-regulated protein expression in phyllodes tumour: comparison with fibroadenoma. Virchows Arch 1998 Oct;433(4):311-4

(48) Elizalde PV, Balana ME, Charreau EH. [Growth hormones and oncogenes in mammary adenocarcinomas induced by medroxyprogesterone acetate in BALB/c mice].[Article in Spanish] Medicina (B Aires) 1997;57 Suppl 2:70-4

(49) Clayton SJ, May FE, Westley BR. Insulin-like growth factors control the regulation of oestrogen and progesterone receptor expression by oestrogens. Mol Cell Endocrinol 1997 Apr 4;128(1-2):57-68

(50) Bentel JM, Lebwohl DE, Cullen KJ, Rubin MS, Rosen N, Mendelsohn J, Miller WH Jr. Insulin-like growth factors modulate the growth inhibitory effects of retinoic acid on MCF-7 breast cancer cells J Cell Physiol 1995 Oct;165(1):212-21.

(51) Eisenbeiss C, Welzel J, Schmeller W. The influence of female sex hormones on skin thickness: evaluation using 20 MHz sonography. Br J Dermatol 1998 Sep;139(3):462-467

(52) Harvell J, Hussona-Saeed I, Maibach HI. Changes in transepidermal water loss and cutaneous blood flow during the menstrual cycle. Contact Dermatitis 1992 Nov;27(5):294-301

(53) Hessemer V, Bruck K. Influence of menstrual cycle on shivering, skin blood flow, and sweating responses measured at night. J Appl Physiol 1985 Dec;59(6):1902-10

(54) Chen L. Induction of osteocalcin gene expression in vitro by progesterone. J Tongji Med Univ 1997;17(2):72-74

(55) MacNamara P, Loughrey HC. Progesterone receptor A and B isoform expression in human osteoblasts. Calcif Tissue Int 1998 Jul;63(1):39-46

(56) Chen L, Foged NT. Differentiation of osteoblast in vitro is regulated by progesterone. J Tongji Med Univ 1996;16(2):83-86

(57) MacNamara P, O'Shaughnessy C, Manduca P, Loughrey HC. Progesterone receptors are expressed in human osteoblast-like cell lines and in primary human osteoblast cultures. Calcif Tissue Int 1995 Dec;57(6):436-441

(58) Heersche JN, Bellows CG, Ishida Y. The decrease in bone mass associated with aging and menopause. J Prosthet Dent 1998 Jan;79(1):14-16

(59) Verhaar HJ, Damen CA, Duursma SA, Scheven BA. A comparison of the action of progestins and estrogen on the growth and differentiation of normal adult human osteoblast-like cells in vitro. Bone 1994 May;15(3):307-311

(60) Tremollieres F, Pouilles JM, Ribot C. [Postmenopausal bone loss. Role of progesterone and androgens].[Article in French] Presse Med 1992 Jun 6;21(21):989-993

(61) Wei LL, Leach MW, Miner RS, Demers LM. Evidence for progesterone receptors in human osteoblast-like cells. Biochem Biophys Res Commun 1993 Sep 15;195(2):525-532

(62) Pensler JM, Langman CB, Radosevich JA, Maminta ML, Mangkornkanok M, Higbee R, Molteni A. Sex steroid hormone receptors in normal and dysplastic bone disorders in children. J Bone Miner Res 1990 May;5(5):493-498

(63) Tremollieres FA, Strong DD, Baylink DJ, Mohan S. Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-2 production. Acta Endocrinol -Copenh 1992 Apr;126(4):329-337

(64) Ribot C, Tremollieres F. [Sex steroids and bone tissue].[Article in French] Ann Endocrinol (Paris) 1995;56(1):49-55

(65) Barengolts EI, Kouznetsova T, Segalene A, Lathon P, Odvina C, Kukreja SC, Unterman TG. Effects of progesterone on serum levels of IGF-1 and on femur IGF-1 mRNA in ovariectomized rats. J Bone Miner Res 1996 Oct;11(10):1406-1412

(66) Slootweg MC, Ederveen AG, Schot LP, Schoonen WG, Kloosterboer HJ. Oestrogen and progestogen synergistically stimulate human and rat osteoblast proliferation. J Endocrinol 1992 May;133(2):R5-R8

(67) Rylance PB, Brincat M, Lafferty K, De Trafford JC, Brincat S, Parsons V, Studd JW. Natural progesterone and antihypertensive action. Br Med J (Clin Res Ed) 1985 Jan 5;290(6461):13-14

(68) Radwanska E. The role of reproductive hormones in vascular disease and hypertension. Steroids 1993 Dec;58(12):605-10

(69) Ottosson UB, Johansson BG, von Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol 1985 Mar 15;151(6):746-50

(70) Chen FP, Lee N, Soong YK. Changes in the lipoprotein profile in postmenopausal women receiving hormone replacement therapy. Effects of natural and synthetic progesterone. J Reprod Med 1998 Jul;43(7):568-74

(71) Kim CJ, Jang HC, Cho DH, Min YK. Effects of hormone replacement therapy on lipoprotein(a) and lipids in postmenopausal women. Arterioscler Thromb 1994 Feb;14(2):275-81

(72) Espeland MA, Marcovina SM, Miller V, Wood PD, Wasilauskas C, Sherwin R, Schrott H, Bush TL. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Circulation 1998 Mar 17;97(10):979-86

 

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