INTRODUCING THE BENEFITS OF PROGESTERONE

by Bradford S. Weeks, M.D.

CONFUSION ABOUT PROGESTERONE

Progesterone is a natural bioidentical horomoe  and it is NOT…

– Progestogen

– Progestin 

– medroxyprogesterone

When your doctor prescribes any of the above and calls it “synthetic progesterone” your doctor is either ignorant or lying. It is not. It is biochemically different and it has many bad side-effects which you don’t get with the real progesterone.

PROBLEMS with SYNTHETICS

This article is not about Progesterone but rather a synthetic near miss knock off: “Progestogen”

Curr Allergy Asthma Rep. 2020 Jan 28;20(1):4. doi: 10.1007/s11882-020-0900-4.

Progestogen Sensitization: a Unique Female Presentation of Anaphylaxis.

Bernstein JA¹.

PURPOSE OF REVIEW: 

Progestogen hypersensitivity (PH) is a condition which typically occurs in women in childbearing years with a spectrum of symptoms ranging from urticaria with or without angioedema, dermatitis to systemic anaphylaxis. (Dr. Weeks reminds you this hypersensitivity is to the synthetic knock off progestogen and NOT to boidentical progesterone)

RECENT FINDINGS: 

Progestogen hypersensitivity (a.k.a. “autoimmune progesterone dermatitis”) symptoms are associated with exogenous progestin exposure(e.g., contraceptive medicines, in vitro fertilization therapy) or endogenous progesterone from progesterone surges during the luteal phase of the menstrual cycle and pregnancy. This condition can be difficult to recognize due to its heterogeneous clinical presentation. The mechanism of PH is believed to be primarily IgE-mediated; however, less commonly other immune responses may be involved. There is now a useful progesterone specific IgE immunoassay to assist in diagnosis and well-defined treatment algorithms that can be used to successfully manage PH. The epidemiology of PH is still poorly elucidated but is likely to be encountered by clinicians and especially allergists given the extensive use of oral contraceptives and increased use of supra-physiologic doses of progesterone required to support pregnancy in IVF. Including PH in the differential diagnosis of women presenting with cyclic hypersensitivity will accelerate diagnosis and successful management of this condition.

TRANSDERMAL IS SUPERIOR TO ORAL 

(less toxicity and better bioavailability) 

J Clin Pharmacol. 2005 Jun;45(6):614-9.

Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product.

Hermann AC¹, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr

SUMMARY: In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.

Executive Summary of Benefits of PROGESTERONE

#1) AntiCancervia Anti-Estrogen and Pro-Testosterone Effects

• Progesterone Promotes Apoptosis (Estrogen Turns it Off)
• Progesterone Upregulates the Gene that Causes Cancer Cells To Die (Estrogen Upregulates the Gene that Cause Cancer Cells to Not Die)
• Progesterone protects men from cancers in general and prostate cancer in particular
• See selected peer reviewed studies below.

#2)  prevents and remedies Osteoporosis

• Progesterone stimulates osteoblastic activity to build bone
• Progesterone inhibits osteoclastic activity 
• Progesterone stimulates osteoblast receptor 
• Progesterone competes for a glucocorticoid osteoblast receptor. 
• Progesteronepromote bone formation 
• Progesterone plays a role in the coupling of bone resorption with bone formation.
• See selected peer reviewed studies below.

#3) Emotional and Cognitive Benefits

• Less anxiety
• Calmer mood
• Zen-like centering of attention 
• Cognitive Enhancement
• See selected peer reviewed studies below.

#4) Neuroprotective 

• Progeterone has neuromodulatory and neuroprotective effects
• Progesterone stimulates neurite outgrowth from dorsal root ganglia sensory neurones
• Progesterone accelerates the maturation of the regenerating axons in cryolesioned sciatic nerve
• Progesterone enhances the remyelination of regenerated nerve fibres
• Progesterone remediates the nervous system via a variety of signaling mechanisms. 
• Progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins.
• Intranasal route of progesterone targets of the brain enhancing local synthesis by neural cells. 
• Progesterone is a strategy for neuroprotection, axonal regeneration, and myelin repair.
• Progesterone (in animal models of demyelination) attenuates myelin loss
• Progesterone reduce clinical symptoms severity in MS, 
• Progesterone modulates inflammatory responses in MS
• Progesterone partially reverse the age-dependent decline in remyelination. 
• Progesterone promotes myelin formation in organotypic cultures of cerebellar slices.
• Progesterone is a pleotropic agent minimizing traumatic brain injury 
• Progesterone and its metabolites decreasing cerebral edema 
• Progesterone modulates p-glycoprotein to maintain blood brain barrier (BBB)
• See selected peer reviewed studies below.

#5)  Stabilization of Blood Sugar

• Weight loss
• Less appetite
• Blunting of glycemic response
• See selected peer reviewed studies below.

#6) Blockage of Adrenalin

• Progesterone lowers blood pressure (hypertension)
• Progesteroneis a viable strategy for preeclampsia management.  (hypertention)
• blocks COMT (catechol O-methyl transferase)
• lowers subjective sense of “stress”
• See selected peer reviewed studies below.

#7) Enhances Fertility and Reduces Miscarriages

• Low serum progesterone levels were strongly correlated with miscarriages
• Progesterone enhances female and male libido 
• See selected peer reviewed studies below.

PEER REVIEWED SCIENTIFIC ARTICLES (ABSTRACTS)

1)  BENEFITS IN CANCER

Altern Ther Health Med. 2017 Nov;23 (6):24-32.

In Defense of Progesterone: A Review of the Literature.

Lieberman A, Curtis L.

Context • The medical literature on the use of progesterone in postmenopausal women is often confusing and contradictory. Some physicians implicate natural progesterone in an increase in the risk of breast cancer. The chemical structure of natural progesterone (P4) is quite different from chemically altered, synthetic chemicals called progestins, which results in different actions at the cell level. 

Objective • The research team intended to review the literature to examine the benefits and safety of natural progesterone and determine whether it can cause an increase or decrease in breast cancer risk.

 Design • A review of the medical literature to examine the benefits and safety of natural progesterone as compared with synthetic progestins. 

Intervention • Studies examined compared controls not receiving hormone therapywith women receiving estrogen alone and in combination with natural progesterone and with various synthetic progestins, such as medroxyprogesterone acetate-the most commonly used synthetic progestin.

 Outcome Measures • Outcome measures included factors such as progression and survival of breast and other cancers and other epidemiological and laboratory data. 

Results • A meta-analysis of 3 studies involving 86 881 postmenopausal women reported that the use of natural progesterone was associated with a significantly lower risk of breast cancer compared with synthetic progestins. 

Anovulation and low levels of serum progesterone have been associated with a significantly higher risk of breast cancer in premenopausal women. Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. 

Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury.

Conclusions • Physicians should have no hesitation prescribing natural progesterone. The evidence is clear that progesterone does not cause breast cancer. Indeed, progesterone is protective and preventative of breast cancer.

Endocr Rev. 2013 Feb;34(1):130-62. doi: 10.1210/er.2012-1043. Epub 2013 Jan 9.

Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer.

Kim JJ¹, Kurita T, Bulun SE.

Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases.

Gan No Rinsho. 1984 Oct;30(13):1633-7.

Changes of hormone receptor status in various treatment for human breast cancer and DMBA tumor of the rat.

Iino Y, , et al.

Abstract

Estrogen receptor (ER) and progesterone receptor (PgR) were measured by sucrose gradient centrifugation before and after various therapies, such as radiation, chemotherapy and hormone therapy. The subjects were 18 advanced or recurrent human breast cancers and 51 DMBA-induced mammary tumors of female SD rats. Changes of hormone receptors and the relationship between receptor levels and the effects of the therapies were examined. Changes of tumor cellularity were also studied in human breast cancers. Some ER-positive tumors changed into ER-negative and others did not. Most ER-negative tumors did not change in ER status. In the responsive cases, receptor levels tended to decline more remarkably and the cellularity of human breast cancer decreased.

2) BENEFITS IN OSTEOPOROSIS

Climacteric. 2018 Aug;21(4):366-374. doi: 10.1080/13697137.2018.1467400. Epub 2018 Jul 2.

Progesterone for the prevention and treatment of osteoporosis in women.

Prior JC^1,2.

Author information

Abstract

Estradiol (E2) is women’s dominant ‘bone hormone’ since it is essential for development of adolescent peak bone mineral density (BMD) and physiological levels prevent the rapid (3-week) bone resorption that causes most adult BMD loss. However, deceasing E2 levels trigger bone resorption/loss. Progesterone (P4) is E2’s physiological partner, collaborating with E2 in every cell/tissue; its bone ‘job’ is to increase P4-receptor-mediated, slow (3-4 months) osteoblastic new bone formation. When menstrual cycles are normal length and normally ovulatory, E2 and P4 are balanced and BMD is stable. However, clinically normal cycles commonly have ovulatory disturbances (anovulation, short luteal phases) and low P4 levels; these are more frequent in teen and perimenopausal women and increased by everyday stressors: energy insufficiency, emotional/social/economic threats and illness. Meta-analysis shows that almost 1%/year spinal BMD loss occurs in those with greater than median (∼31%) of ovulatory disturbed cycles. Prevention of osteoporosis and fragility fractures requires the reversal of stressors, detection and treatment of teen-to-perimenopausal recurrent cycle/ovulatory disturbances with cyclic oral micronized progesterone. Low ‘Peak Perimenopausal BMD’ is likely the primary risk for fragility fractures in later life. Progesterone plus estradiol or other anti-resorptive therapies adds 0.68%/year and may be a highly effective osteoporosis treatment. Randomized controlled trials are still needed to confirm progesterone’s important role in women’s bone formation.

Endocr Rev. 1990 May;11(2):386-98.

Progesterone as a bone-trophic hormone.

Prior JC¹.

Author information

Abstract

Experimental, epidemiological, and clinical data indicate that progesterone is active in bone metabolism. Progesterone appears to act directly on bone by engaging an osteoblast receptor or indirectly through competition for a glucocorticoid osteoblast receptor. Progesterone seems to promote bone formation and/or increase bone turnover. It is possible, through estrogen-stimulated increased progesterone binding to the osteoblast receptor, that progesterone plays a role in the coupling of bone resorption with bone formation. A model of the interdependent actions of progesterone and estrogen on appropriately-“ready” cells in each bone multicellular unit can be tied into the integrated secretions of these hormones within the ovulatory cycle. Figure 5 is an illustration of this concept. It shows the phases of the bone remodeling cycle in parallel with temporal changes in gonadal steroids across a stylized ovulatory cycle. Increasing estrogen production before ovulation may reverse the resorption occurring in a “sensitive” bone multicellular unit while gonadal steroid levels are low at the time of menstrual flow. The bone remodeling unit would then be ready to begin a phase of formation as progesterone levels peaked in the midluteal phase. From this perspective, the normal ovulatory cycle looks like a natural bone-activating, coherence cycle. Critical analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This review provides the preliminary basis for further molecular, genetic, experimental, and clinical investigation of the role(s) of progesterone in bone remodeling. Much further data are needed about the interrelationships between gonadal steroids and the “life cycle” of bone. Feldman et al., however, may have been prophetic when he commented; “If this anti-glucocorticoid effect of progesterone also holds true in bone, then postmenopausal osteoporosis may be, in part, a progesterone deficiency disease.”

3) BENEFITS IN MOOD DISORDER

a) ANTI-ANXIETY

Horm Behav. 2018 Jun;102:34-40. doi: 10.1016/j.yhbeh.2018.04.008. Epub 2018 Apr 24.

Progesterone and women’s anxiety across the menstrual cycle.

Reynolds TA¹, Makhanova A², Marcinkowska UM³, Jasienska G⁴, McNulty JK⁵, Eckel LA⁶, Nikonova L⁷, Maner JK⁸.

Abstract

Animal models and a few human investigations suggest progesterone may be associated with anxiety. Progesterone naturally fluctuates across the menstrual cycle, offering an opportunity to understand how within-person increases in progesterone and average progesteronelevels across the cycle correspond to women’s anxiety. Across two longitudinal studies, we simultaneously modeled the between- and within-person associations between progesterone and anxiety using multilevel modeling. In Study 1, 100 Polish women provided saliva samples and reported their anxiety at three phases of the menstrual cycle: follicular, peri-ovulatory, and luteal. A significant between-person effect emerged, revealing that women with higher average progesterone levels across their cycles reported higher levels of anxiety than women with lower progesterone cycles. This effect held controlling for estradiol. In Study 2, 61 American women provided saliva samples and reported their attachment anxiety during laboratory sessions during the same three cycle phases. A significant between-person and within-person association emerged: women with higher average progesterone levels reported higher levels of attachment anxiety, and as women’s progesterone levels increased across their cycles, so too did their attachment anxiety. These effects held controlling for cortisol. In sum, both studies provide support for a link between menstrual cycle progesterone levels and subjective anxiety.

b) JEALOUSY

Psychoneuroendocrinology. 2019 Dec 20;113:104553. doi: 10.1016/j.psyneuen.2019.104553. [Epub ahead of print]

Does women’s anxious jealousy track changes in steroid hormone levels?

Hahn AC¹, DeBruine LM², Pesce LA³, Diaz A³, Aberson CL³, Jones BC².

Author information

Abstract

Findings for progesterone and anxiety in non-human animals led to the hypothesis that women’s interpersonal anxiety will track changes in progesterone during the menstrual cycle. There have been few direct tests of this hypothesis, however. Consequently, we used a longitudinal design to investigate whether interpersonal anxiety (assessed using the anxious jealousy subscale of the relationship jealousy questionnaire) tracked changes in salivary steroid hormones during the menstrual cycle in a large sample of young adult women. We found no evidence for within-subject effects of progesterone, estradiol, their interaction or ratio, testosterone, or cortisol on anxious jealousy. There was some evidence that other components of jealousy (e.g., reactive jealousy) tracked changes in women’s cortisol, however. Collectively, these results provide no evidence for the hypothesis that interpersonal anxiety tracks changes in progesterone during the menstrual cycle.

(Dr. Weeks’ Comment:  This study was not done with men re male jealousy for some reason….)

#4) BENEFITS FOR NEUROLOGICAL SYSTEM 

Rev Reprod. 2000 Sep;5(3):189-99.

Role of progesterone in peripheral nerve repair.

Koenig HL¹, Gong WH, Pelissier P.

Author information

Abstract

Progesterone is synthesized in the peripheral nervous system in glial cells. The functions of progesterone are indicated by the findings that it stimulates neurite outgrowth from dorsal root ganglia sensory neurones in explant cultures, accelerates the maturation of the regenerating axons in cryo-lesioned sciatic nerve, and enhances the remyelination of regenerated nerve fibres. The formation of myelin sheaths around axons is a sexually dimorphic process, as the sheaths are thicker in female than in male regenerating nerves. The progesterone-induced myelination is probably mediated by progesterone receptors, as it is impaired by mifepristone (RU486), a progesterone antagonist. The stimulation of neurite growth in the peripheral nervous system may be mediated by a progesterone metabolite, 5alpha-tetrahydroprogesterone, through GABA(A) receptors.

Front Neurosci. 2012; 6: 10. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274763/

Progesterone Synthesis in the Nervous System: Implications for Myelination and Myelin Repair

Michael Schumacher et al

Progesterone is well known as a female reproductive hormone and in particular for its role in uterine receptivity, implantation, and the maintenance of pregnancy. However, neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction. Within the nervous system, its neuromodulatory and neuroprotective effects are much studied. Although progesterone has been shown to also promote myelin repair, its influence and that of other steroids on myelination and remyelination is relatively neglected. Reasons for this are that hormonal influences are still not considered as a central problem by most myelin biologists, and that neuroendocrinologists are not sufficiently concerned with the importance of myelin in neuron functions and viability. The effects of progesterone in the nervous system involve a variety of signaling mechanisms. The identification of the classical intracellular progesterone receptors as therapeutic targets for myelin repair suggests new health benefits for synthetic progestins, specifically designed for contraceptive use and hormone replacement therapies. There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins. The delivery of progesterone however represents a challenge because of its first-pass metabolism in digestive tract and liver. Recently, the intranasal route of progesterone administration has received attention for easy and efficient targeting of the brain. Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair.

Progesterone and Nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex

Martine el-Etr,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237628/

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 anti-inflammatory 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.

Pediatr Crit Care Med. 2015 Mar; 16(3): 236–244. 

Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury

Courtney L. Robertson, MD, et al 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806367/

Over the last 25 years, many preclinical studies have demonstrated neuroprotection by progesterone after TBI in adult animal models (4–13). Dr. Stein and colleagues began investigating progesterone after observing that female rats recovered better than male rats after TBI (14). In initial studies, they compared three groups of adult rats (normal male rats, normally cycling female rats in proestrus, and pseudopregnant female rats with high circulating progesterone) (15). They found that normal female rats had less brain edema at 24h after TBI compared to male rats, and that the pseudopregnant females had remarkably little brain edema compared to the other 2 groups. Follow-up studies showed that exogenous treatment of male rats with progesterone reduced cerebral edema, lesion volume and neuronal loss after TBI (15). Similarly, Bramlett and Dietrich compared male rats, normal female rats and ovariectomized female rats showing the smallest lesion volumes in normal females compared to the other 2 groups (16). Dr. Stein’s group also showed that the therapeutic window for progesterone could be up to 24h after TBI, when targeting cerebral edema (17), and that there is a u-shaped dose response curve for improving cognitive outcomes, including memory acquisition in the Morris water maze (18). In addition they described potentially detrimental symptoms of abrupt progesterone withdrawal that may warrant tapering (19). Other investigators have confirmed the neuroprotective properties of progesterone using a variety of TBI models in adult animals. We performed a Pubmed search of all original preclinical research studies of progesterone use in adult TBI published between 1992 and 2013. The 46 identified studies are summarized in Supplemental Digital Content – Table 1. In addition, a recent preclinical systematic review summarized the key aspects of progesterone treatment for neuroprotection after TBI and cerebral ischemia in adult animals, looking at effects on lesion volume (20). The main finding was that progesterone was neuroprotective, but limitations in the literature were identified, including insufficient examination of dose-response relationships, therapeutic windows, and evaluation in female or aged adult animals.

The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of TBI. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children, and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, statue epilepticus).

#5)  SUPPORTS BLOOD SUGAR STABILITY 

Neuroscience. 2017 May 14;350:1-12. doi: 10.1016/j.neuroscience.2017.03.007. Epub 2017 Mar 14.

Progesterone modulates diabetes/hyperglycemia-induced changes in the central nervous system and sciatic nerve.

Atif F¹, Prunty MC¹, Turan N², Stein DG¹, Yousuf S³.

Author information

Abstract

We investigated the effect of progesterone (P4) treatment on diabetes/hyperglycemia-induced pathological changes in brain, spinal cord and sciatic nerve tissue in male rats. Animals were rendered hyperglycemic by a single dose of streptozotocin (STZ). P4 treatment was started after hyperglycemia was confirmed and body weight and blood glucose levels were monitored once/week for 5weeks. Rats underwent behavioral testing at week 5 and were then euthanized for histology. We assessed the expression of markers of angiogenesis (vascular endothelial growth factor (VEGF)), inflammation (interleukin-6 (IL-6)) and tissue injury (CD11b, NG2, COX2 and matrix metalloproteinase-2 (MMP-2)) in the brain, spinal cord and sciatic nerve. We also examined the regenerative effect of P4 on pathological changes in intra-epidermal nerve fibers (IENF) of the footpads. Diabetes/hyperglycemia led to body weight loss over 5weeks and P4 treatment reduced this loss. At week 5, blood-glucose levels were significantly lower in the P4-treated diabetic group compared to vehicle. Compared to sham or P4-treated groups, the diabetic vehicle group showed hyperactivity on the spontaneous locomotor activity test. Western blot data revealed upregulation of VEGF, IL-6, CD11b, NG2, COX2 and MMP-2 levels in the vehicle group and P4 treatment normalized these expression levels. IENF densities were reduced in the vehicle group and normalized after P4 treatment. We conclude that P4 can reduce some of the chronic pathological responses to STZ-induced diabetes.

Life Sci. 2019 Dec 1;238:116979. doi: 10.1016/j.lfs.2019.116979. Epub 2019 Oct 21.

Effects of progesterone on glucose uptake in neurons of Alzheimer’s disease animals and cell models.

Wu H¹, Wu ZG², Shi WJ³, Gao H⁴, Wu HH⁵, Bian F⁶, Jia PP⁶, Hou YN⁷.

Author information

Abstract

AIMS: 

Alzheimer’s disease (AD) is closely related to abnormal glucose metabolism in the central nervous system. Progesterone has been shown to have obvious neuroprotective effects in the pathogenesis of AD, but the specific mechanism has not been fully elucidated. Therefore, the purpose of this study was to investigate the effect of progesterone on the glucose metabolism of neurons in amyloid precursor protein (APP)/presenilin 1 (PS1) mice and Aβ-induced AD cell model.

MATERIALS AND METHODS: 

APP/PS1 mice were treated with 40 mg/kg progesterone for 40 days and primary cultured cortical neurons were treated with 1 μM progesterone for 48 h.Then behavior tests,2-NBDG glucose uptake tests and the protein levels of glucosetransporter 3 (GLUT3), GLUT4, cAMP-response element binding protein (CREB) and proliferator-activated receptor γ (PPARγ) were examined.

KEY FINDINGS: 

Progesterone increased the expression levels of GLUT3 and GLUT4 in the cortex of APP/PS1 mice, accompanied by an improvement in learning and memory. Progesterone increased the levels of CREB and PPARγ in the cerebral cortex of APP/PS1 mice. In vitro, progesterone increased glucose uptake in primary cultured cortical neurons, this effect was blocked by the progesterone receptor membrane component 1 (PGRMC1)-specific blocker AG205 but not by the progesterone receptor (PR)-specific blocker RU486. Meanwhile, progesterone increased the expression of GLUT3, GLUT4, CREB and PPARγ, and AG205 blocked this effect.

SIGNIFICANCE: 

These results confirm that progesterone significantly improves the glucose metabolism of neurons.One of the mechanisms of this effect is that progesterone upregulates protein expression of GLUT3 and GLUT4 through pathways PGRMC1/CREB/GLUT3 and PGRMC1/PPARγ/GLUT4.

6)  BLOCKS ADRENALIN 

Placenta. 2018 Feb;62:16-24. doi: 10.1016/j.placenta.2017.12.004. Epub 2017 Dec 7.

Progesterone attenuates hypertension and autoantibody levels to the angiotensin II type 1 receptor in response to elevated cadmium during pregnancy.

Zhang Q¹, Huang Y², Zhang K³, Yan Y⁴, Wu J¹, Wang F¹, Zhao Y¹, Xu H¹, Jiang W⁵, Yu D¹, Chen Y⁴, Ye D⁴.

Author information

Abstract

INTRODUCTION: 

Preeclampsia is associated with the presence of pathogenic angiotensin-receptor-activating autoantibodies. Cadmium is an increasingly prevalent environmental pollutant that can mimic oestrogens, which may enhance immunoglobulin production. Progesterone exerts opposite effects to oestrogen.

METHODS: 

We measured the levels of cadmium and progesterone in preeclamptic patients and controls. Pregnant rats exposed to cadmium (0.125 mg/kg body weight) from gestational day 9-12 were treated with/without progesterone (3 mg/kg) beginning from gestational day 9 to delivery. We analysed the main features of preeclampsia and circulating level of the angiotensin II type 1 receptor agonistic autoantibody. We also measured the expression of activation-induced cytosine deaminase in B cells.

RESULTS: 

There were higher cadmium levels and lower progesterone levels in the blood of preeclamptic women than in the blood of those with a healthy pregnancy. Based on this finding, a rat model of preeclampsia was established by intraperitoneally administrating low-dose cadmium on gestational days 9-12. Rats were then treated with/without progesterone. Key features of preeclampsia, including hypertension, proteinuria and placental abnormalities, appeared in pregnant rats after cadmium injection and improved after treatment with progesterone. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor-agonistic autoantibodies, by increasing the expression of activation-induced cytosine deaminase in B cells; progesterone exerted an opposite effect.

CONCLUSION: 

Cadmium induced immune abnormalities that may be a key pathogenic contributor to preeclampsia. Progesterone supplementation to correct hormonal imbalance may be a viable strategy for preeclampsia management.

Br J Pharmacol. 1971 Feb;41(2):187-97.

Effects of progesterone on cardiovascular responses to amines and to sympathetic stimulation in the pithed rat.

Fozard JR.

Abstract

1. Blood pressure and heart rate responses to adrenaline, noradrenaline, tyramine, 5-hydroxytryptamine and stimulation of the spinal sympathetic outflow were measured in pithed rats pretreated either with progesterone (20 mg/kg daily for 14 days) or the vehicle solution of ethyl oleate.2. Pretreatment with progesterone increased the durations but not the magnitudes of the blood pressure and heart rate responses to adrenaline and that phase of the response to sympathetic stimulation attributable to amine release from the adrenal medulla.3. Responses to noradrenaline, tyramine, 5-hydroxytryptamine and that phase of the response to sympathetic stimulation associated with amine release from the sympathetic nerves were not significantly different in the two groups.4. Pyrogallol (5 mg/kg) increased the duration but not the magnitude of responses to adrenaline, noradrenaline and sympathetic stimulation in both experimental groups. The increases in duration were consistently less in animals pretreated with progesterone than in controls.5. Pretreatment with progesterone did not affect the total amount of radioactivity nor the proportion of catechol to non-catechol metabolites excreted in the urine during a period of 7.25 h following an intraperitoneal injection of (+/-) isoprenaline-7-(3)H.6. It is concluded that the effects of progesterone may result from a localized decrease in catechol O-methyl transferase activity within the cardiovascular system.

7) BENEFITS  re FERTILITY and REDUCED  MISCARRIAGE

J Gynecol Obstet Hum Reprod. 2020 Feb 26:101721. doi: 10.1016/j.jogoh.2020.101721. [Epub ahead of print]

Serum progesterone levels could predict diagnosis, completion and complications of miscarriage.

Blavier F¹, Blockeel C², Cools W³, Faron G⁴, Santos-Ribeiro S⁵, Breugelmans M⁴, Adriaensen P⁶, Fuchs F⁷, Gucciardo L⁴.

Author information

Abstract

BACKGROUND: 

Low serum progesterone levels were strongly correlated with miscarriages in several publications and with completion of miscarriage in one paper. This study evaluated several parameters, predominantly serum progesterone, as predictors for miscarriages, their swift non-surgical completion and their complications.

BASIC PROCEDURES: 

Suspected or confirmed non-viable pregnancies with available concomitant serum progesterone measurements were retrospectively reviewed. The performance of serum progesterone, either alone or combined with other parameters, to predict viability, surgical removal and delay of non-surgical evacuation of non-viable pregnancy and complications, was analysed by logistic regression combined with Akaike and Bayesian information criteria, likelihood, receiver operated characteristic (ROC) curves, Mann-Whitney test and Fisher’s exact test.

MAIN FINDINGS: 

From 151 included pregnancies, 104 (68.9%) were non-viable with 91 completions of miscarriage without surgery. The probability of viability was correlated linearly and curvilinearly with serum progesterone (p < 0.001). The probability of surgical removal, and the delay before non-surgical evacuation, showed a linear relationship with progesterone. No complication occurred when progesterone levels remained below 10 µg/L, while its rates were 9.5% of non-viable pregnancies with progesterone levels between 10 and 20 µg/L and 26.7% of cases with progesterone levels above 20 µg/L. Combined with progesterone, either “parity” or “history of miscarriage” improved the prediction of viability, “history of supra-isthmic uterine surgery” improved the prediction of surgery and “history of miscarriage” improved the prediction of delayed non-surgical evacuations.

CONCLUSION: 

Serum progesterone can probably predict the odds of miscarriages, surgical removal, delayed non-surgical evacuation and complications, with potential improvements when different predictors are combined.

CONFUSION ABOUT PROGESTERONE

Progesterone is a natural bioidentical horomoe  and it is NOT…

– Progestogen

– Progestin 

– medroxyprogesterone

PROBLEMS with SYNTHETICS

This article is not about Progesterone but rather a synthetic near miss knock off: “Progestogen”

Curr Allergy Asthma Rep. 2020 Jan 28;20(1):4. doi: 10.1007/s11882-020-0900-4.

Progestogen Sensitization: a Unique Female Presentation of Anaphylaxis.

Bernstein JA¹.

PURPOSE OF REVIEW: 

Progestogen hypersensitivity (PH) is a condition which typically occurs in women in childbearing years with a spectrum of symptoms ranging from urticaria with or without angioedema, dermatitis to systemic anaphylaxis. Herein, a clinical case of PH is presented followed by a discussion on the evaluation, diagnosis, and management of PH.

RECENT FINDINGS: 

Progestogen hypersensitivity (a.k.a. “autoimmune progesterone dermatitis”) symptoms are associated with exogenous progestin exposure(e.g., contraceptive medicines, in vitro fertilization therapy) or endogenous progesterone from progesterone surges during the luteal phase of the menstrual cycle and pregnancy. This condition can be difficult to recognize due to its heterogeneous clinical presentation. The mechanism of PH is believed to be primarily IgE-mediated; however, less commonly other immune responses may be involved. There is now a useful progesterone specific IgE immunoassay to assist in diagnosis and well-defined treatment algorithms that can be used to successfully manage PH. The epidemiology of PH is still poorly elucidated but is likely to be encountered by clinicians and especially allergists given the extensive use of oral contraceptives and increased use of supra-physiologic doses of progesterone required to support pregnancy in IVF. Including PH in the differential diagnosis of women presenting with cyclic hypersensitivity will accelerate diagnosis and successful management of this condition.

TRANSDERMAL IS SUPERIOR TO ORAL 

(less toxicity and better bioavailability) 

J Clin Pharmacol. 2005 Jun;45(6):614-9.

Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product.

Hermann AC¹, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr.

Author information

Abstract

Progesterone products are available in prescription form as well as over-the-counter (OTC) topical preparations sold for “cosmetic” uses. In a randomized study design, the authors compared the drug exposure from an OTC progesterone cream to a Food and Drug Administration-approved oral preparation at the labeled daily doses recommended for each product. Twelve healthy postmenopausal women received 200-mg oral progesterone capsules once daily for 12 days or progesterone cream 40 mg twice daily for 12 days. At steady state (day 12 of each phase), whole-blood samples were collected over 24 hours (oral progesterone) or 12 hours (topicalprogesterone) and assayed for total progesterone concentration. No significant differences were found in dose-normalized 24-hour progesterone exposure comparing the cream to oral capsules (median AUC(0-24) 12.5 ng x h/mL vs 10.5 ng x h/mL, respectively; P = .81). In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.