progesterone in postmenopausal women A) To control hot flush B) Night sweat C) osteoporosis

Let us discuss on role of progesterone in postmenopausal women A) To control hot flush B) Night sweat C) To prevent osteoporosis D) Progesterone in Alzheimer ’s disease, Auto immune diseases, Multiple sclerosis? What is the action of Progesterone in human brain??? ??

Actions of each progesterone are not alike!!! Therefore a judicious selection of use of synthetic progestogens which are in clinical use during the menopause and post menopause, are warranted.    Newer evidence from molecular and genomic studies suggests that not all progestins have the same effect.

Each pro­gestin has its own biocharcteristics regarding breast cancer as in other clinical conditions.

. Progesterone has been shown to have neuroprotective effects and is used in vari­ous brain injuries .Progesterone has both genomic and non-genomic actions. A)   What about genomic action of progesterones??? Ans:     The genomic action is the classical reaction whereby the hormone progesterone, acting as a ligand, con­nects to its receptor in the nucleus and initiates new mRNA protein synthesis. This is a relatively slow process.

 

B)   What about nongenomic action of progesterones?? The rapid action of progestogens is due to non-genomic actions in which intracellular signaling pathways are activated resulting in alteration of ions fluxes and intracellular calcium concentration within seconds . The non genomic actions also induce second messengers, such as cyclic nucleotides and extracellular regulated kinases .These actions are specific to each individual progestogen.

 

 

 Which progesterone –When? How best to select type of progesterone in menopausal years?? As synthetic progestogens differ in actions, proper selection is necessary for successful therapy in treating 1) menopausal symptoms or 2) reducing the risk of dis­eases associated with the menopause.

Use of synthetic progestogens is in clinical use during the menopause and post menopause, most notably are as follows A)  Hot flush  adjunct to estrogen replacement therapy but no increased prevalence of Breast cancer .

Progestogens are necessary in order to prevent endo­metrial hyperplasia caused by unopposed estrogen and in recent years, large clinical trials have shown that the association of progestins with estrogen in HRT might raise the risk of breast cancer, but this risk was not confirmed in ongoing clini­cal studies which have not shown that trend .

B) Postmenopausal use of Progestogens to prevent Osteoporosis!!

Progestogens alone have a very limited effect on bone mineral density (BMD). But, pretreatment with estrogen for 4-7 days has been shown to induce progesterone receptors in osteoblasts .

This explains the beneficial effect on BMD, in all clini­cal trials in which progestogens were added to estrogen.

What about MPA?? Ans: Medroxyprogesterone acetate (MPA) decreases BMD, both in the hips and spine, in the first 2 years of use, followed by a slight increase.

What about Primolut N/ Crina CR with low dose of natural orstrogens ??  Ans :- Norethisterone is a synthetic progestin derived from 19-nortestosterone. It binds and activates the progesterone receptor twice as much as progesterone itself, with low androgenic and estrogenic activities attributed to its metabolites The effect of norethisterone acetate (NETA) with a low dose of 17(3-estardiol)  on BMD has been investigated in a randomized placebo control study .There was a significant increase in BMD both in the lumbar spine (5.2 %) and the hip (3.1 %) compared to the placebo group (-0.9%).

Serum concentration of osteocalcin decreased by approximately 34 %, bone-specific alkaline phosphatase decreased by about 30 %, and C-terminal propepetide of type I collagen decreased by 20 %. Controversially, inhibition of the nuclear progesterone receptor has been found to augment bone mass, resulting in higher BMD .

C) Use of progesterone in ht flush alone??Role of synthetic progesterone  in control of Hot Flush and Night Sweats?? Ans: In this settings best progesterone will be nightly micronized progesterone (300 mg) or medroxy­progesterone acetate (MPA) 10 mg/day. that micronized progesterone and pregnane derivates are safer with regard to VTE risk.

These have been shown to cause an overall decrease in the number of daily hot flushes and night sweats by 59 %. Extension of this study has shown that micronized progesterone is also effective for severe vasomotor symptoms and that progesterone withdrawal is not followed by a rebound increase in vasomotor symptoms .A similar effect has been shown for medroxy­progesterone acetate (MPA) 10 mg/day. But  MPA, by activating glucocorticoid receptors, potentiate the vascular effects of thrombin

A study in which patients received either conjugated equine estrogen (CEE), (0.6 mg/day) or MPA for 1 year. MPA was found to be equivalent to CEE in the control of vasomotor symptoms in women. Therefore progestogens(MPA) can be initiated  soon after the surgery of TAH & BSO with identical efficacy like combined HRT.

 

 

D) Vasomotor symptoms: Drug selection of steroid group!!!! A great dilemma –Only Oestrogens, only Progesterone or combined Oetsrogen & progesterone ?? Ans & Logic:- Oral progestins have been shown to be effective for vasomotor symptoms in several randomized placebo controlled trial .Mode of action of  HRT to control hot flush which is fortunately less common in our country? Mode of action of each hormone?? Estrogen alleviates hot flushes by lowering levels of serotonin and noradrenaline in the brain .Progestogens may act in a different manner. Progesterone acts on the hypothalamus changing the frequency of LH pulses, increasing basal temperature and stimulating respiration. Therefore progesterone and progestins have various effects on the hypothalamus, from which hot flushes are thought to generate

Risk of combined HRT ??? Does Progesterone promotes Venous Thromboembolism?? Micronized progesterone and pregnane derivates are safer with regard to VTE risk.

Progestins, when given alone (e.g. progestin only contraceptive pills), carry little, if any, risk of VTE. Randomized controlled studies and meta-analyses of observational studies suggest that the risk of venous thrombo-embolism (VTE) is higher among users of combined estrogen and progestogen than among users of estrogen alone. Oral estrogens increase the VTE risk while transdermal estrogens appear to be safe with respect to thrombotic risk .However, MPA, by activating glucocorticoid receptors, potentiate the vascular effects of thrombin .The ESTHER study (Estrogen and Thromboembolism Risk) looked into the risk of VTE in French post­menopausal women treated with HRT. This study was the first to establish a differen­tial association of VTE risk related to the progestogen used. The results were irrespective of the route of estrogen administration. The results showed that micronized progesterone and pregnane derivates are safer with regard to VTE risk. The norpregnane derivatives were associated with a significant increase in VTE risk

The norpregnanes are potent progestogens with antiestrogenic activity. Women suffering from hyperestrogenic effects, such as breast tenderness or endometrial hyperplasia are more likely to benefit from this type of progestogens.

F) What are the actions of Progesterone on  the Brain??

Progesterone is metabolized in the brain by 5a-reductase to 5a-dihydroprogesterone. This in turn is further metabolized by 3a-hydroxysteroid dehydrogenase to the neurosteroid allopregnanolone.

The neurosteroids are modulatory ligands for a variety of neurotransmitters and nuclear steroid hormone receptors. Allopregnanolone crosses the blood-brain bar­rier. It has been shown in rodents, that allopregnanolone is an efficacious prolifera­tive agent (both in vitro and in-vivo studies)  It also decreases amyloid protein in human neural stem cells .Progesterone metabolites exert considerable seda­tive effects after binding to the GABAA receptor . Neurosteroids such as preg- nanolone affect synaptic functions and myelinization. Their action is mediated through inhibition of the glycogen synthase kinase (GSK-3[5) pathway (much like

most bipolar mood stabilizers such as lithium) .Neurosteroids are modulatory ligands for a variety of neurotransmitters and nuclear steroid hormone receptors. Progesterone has been shown to reduce inflammatory reactions commonly seen in MS, by the direct effect of progesterone on astrocytes and microglia

 

H) How efcetive is Progesterone in Alzheimer’s Disease??

Estradiol increases the expression of the progesterone-synthesizing enzymes. Estradiol increases the expression in the hypothalamus, and especially in the astro­cytes. Astrocytes are the most active steroidogenic cells in CNS and contribute to neuro-protection Treatment with different types of progestogens found that these compounds may promote neurogenesis, neural survival, myelinization and increases memory .There is some data that suggests that allopregnanolone may maintain the regenerative ability of the brain and also can modify the progression of Alzheimer’s disease .Progesterone has been shown to improve impaired axonal transport, a key event of the aging brain. Reduced axonal transport has been pro­posed to play an early and causative role in the development of Alzheimer’s disease. In mouse models, reduced axonal transport may lead to aberrant amyloid-p peptide formation and subsequently to neurodegeneration .

Traumatic Brain Injury (TBI)

In TBI, whether post menopausal or not, the use of progesterone was found to be effective in reducing brain damage.. In brief, data is available showing that progesterone reduces edema, restores the blood-brain barrier, protects against secondary neuronal death and promotes behavioral recovery after TBI  A phase II clinical trial, the ProTECT study, has shown more than 50 % reduction in mortality in mortality in severe TBI and a statistically significant improvement in functional outcome in patients with moderate BTI, when treatment was administered no later than 2 h after sus­taining BTI

 Take home message about Combined HRT or progesterone alone in hot flush & osteoporosis

Progesterone and progestogens have a significant role in various clinical situa­tions throughout life. As the novel actions of progestogens are elucidated it is clear that these hormones have influence on the outcome of many clinical conditions.

It is important to bear in mind that there is no class effect of all these compounds. Each has its own clinical, biochemical and molecular specific effects. In depth knowledge of the physio-pathological effects of each progestogen will enable their better use in many clinical conditions such as hot flushes, brain trauma, sleep disorder and more. The most serious clinical side effects are the raised risk of breast cancer associated with some progestogens (e.g. MPA) but not with others such as micronized progesterone. MPA has also been shown to inhibit some of the beneficial effects of estradiol on the CNS. The fact that numerous coregulators affect the end result of ligand-progesterone receptors (both nuclear and mem­brane) indicates to the complexities of progesterone/progestogens actions. Receptor affinity alone does not determine potency. Our present understanding is that the affinity, potency and efficacy of progestogens are substantially different between the different types of progestogens and are tissue specific.

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