Articles to help WP recovery

Given our unusual situation of over pregnancy levels of progesterone on the WP (enough to create linea negra of pregnancy) we are encountering many problems. This area of the website will host scientific literature excerpts for women and doctors to understand how to deal with this never before seen situation of so many women with massive progesterone poisoning.   Many of us are currently in Wash Out and we find the detox process varies.  Please read the article Progesterone Dominance, An Insidious Problem for discussion about the issue of absorption, clearance and the inaccuracy of serum and even saliva testing.  


Progesterone and higher levels of estrogen in the breast.  Women on the WP often complained of tenderness in the breast.  


Sore kidneys and extreme edema

Progesterone and body fluids.


Sugar and carbohydrate craving

Progesterone and glucose homeostasis


Kidney stones

 Osteopontin, calcium stone formation in the kidneys and high doses of progesterone

 See Linette’s story of her ER visit with kidney stones on day 21 which is the highest day for progesterone.


Cardiovascular issues: Racing heart, elevated blood pressure.   Estrogen, progesterone and the renin-angiotensin-aldosterone system.


Chin whiskers and other signs of masculinity: The human kidney has the enzyme machinery to remove pregnancy surplus levels of progesterone via biosynthesis into androgens.  (Some women developed male pattern balding and T-tops at the hairline.  Saliva and serum testing revealed extremely high testosterone levels in women who were not supplementing with testosterone and had low testosterone levels before the protocol.  This was not the case in all women who lost hair and developed whiskers.)


Sedation, sleepiness, depression Progesterone metabolites are neuroactive steroids with hypnotic anesthetic properties.




Literature Excerpts by Bent Formby, PhD. 




Progesterone and higher levels of estrogen in the breast.


Some interesting new data about progesterone and the possible risk for developing breast cancer in women exposed to supraphysiologic WP doses of progesterone.


Estrogen is a key regulator of normal breast physiology as well as a major risk factor for breast cancer carcinogenesis (1,2). Several studies have suggested that the concentrations of estrogen in the breast not only originate from the ovaries but that the breast itself produces a significant portion of tissue estrogens (3). For example, in breast cancer tissue as well as in nipple aspirate from normal breast, tissue estrogen levels have been found to be significantly higher than plasma levels (4). All enzymes necessary for estrogen biosynthesis – aromatase, steroid sulphatase and 17beta-hydroxysteroid dehydrogenase – have been shown to be present in normal breast tissue (5). Now, in a new study (6) it was documented that normal cycling women with high plasma progesterone levels, verifying the mid-luteal phase of the menstrual cycle, had significantly higher extracellular levels of 17beta-estradiol in breast tissue in vivo compared with subcutaneous fat. In women with low progesterone levels, representing non-ovulating women or women in the follicular phase, there was no difference in 17beta-estradiol levels between breast tissue and subcutaneous fat. These data suggest that progesterone strongly stimulates the de novo production of 17beta-estradiol in normal breast tissue. Hence, increased plasma levels of progesterone significantly correlated with enhanced breast tissue production of 17beta-estradiol. In this study microdialysis was used to determine the local levels of estrogens in normal breast tissue.


Women on the WP often complained of tenderness in the breast. Could this situation be explained by an increased local breast tissue biosynthesis of 17beta-estradiol stimulated by high doses of progesterone?


1. Beral V. Lancet 2003; 362:376-82

2. Rossouw JE et al. JAMA 2002; 288:321-33

3. Geisler J. J Steroid Biochem Mol Biol 2003; 86:245-53

4. Chatterton jr RT et al. J Steroid Biochem Mol Biol 2003; 86:159-66

5. Chen S et al. J Steroid Biochem Mol Biol 2002; 83:93-99

6. Dabrosin C. J Endocrinol 2005; 187:103-8


Bent Formby, PhD. 10/25/06





Progesterone and body fluids.


60% of the body weight of a normal person is water. 40% is the intracellular fluid and 20% is the extracellular divided into interstitial compartment (15%) and blood (5%). Edema is accumulation of water in the interstitial compartment. Fluid in general flows between compartments dependent on osmotic concentrations of electrolytes (Na, K, Cl and phosphate) and proteins. The kidneys are the major regulator of blood volume by regulating amounts of salt filtered out and reabsorbed. Natriuretic peptide hormones from the heart (ANP), brain (BPN) or vascular endothelial cells (CNP) act on the kidneys by their specific receptors (NP-Rs) to increase excretion of Na. When Na is excreted also water is excreted. In humans the ANP-receptor is up-regulated by estrogen and down-regulated by progesterone. Hence, ANP plasma concentrations are lowest in the luteal phase and during pregnancy. Estrogen may modify progesterone-mediated inhibition of ANP. Therefore, modulation of ANP may be a mechanism by which estrogen and progesterone alter body fluid dynamics (1). In a recent study from a research group at Yale University (2) is was found that progesterone increases plasma volume independent of estrogen. When the plasma concentrations of progesterone during an experimental period of 9 days was increased from 2.5 to 12.0 ng/ml, the plasma volume significantly increased from 43 ml/kg to 47 ml/kg or 9.3%. These data tell us that progesterone attenuate the renal effects of ANP which reflects a physiological adjustment to facilitate fluid/electrolyte expansion seen during pregnancy. Long-term exposure to pregnancy levels of progesterone (WP?) may introduce edema.


1. Stachenfeld NS et al, Estrogen and progesterone effects on transcapillary fluid dynamics. Am J Physiol Regulatory Integrative Comp Physiol 2001; 281:R1319-29


2. Stachenfeld NS et al. Progesterone increases plasma volume independent of estradiol. J Appl Physiol 2005; 98:1991-97




Progesterone and glucose homeostasis.


Human insulin regulates blood sugar. The insulin function is mediated by the insulin receptor expressed on the surface of cells. Inside the cells plasma membrane the insulin signal is mediated by insulin receptor substrates or IRS. When the signal is executed sugar as glucose is taken up by the cell and metabolized into fat or energy. Diabetics have low expression of IRS.

Progesterone up-regulates the concentration of IRS-2 by stimulation the transcription of the IRS-2 gene (1). High levels of progesterone lower concentrations of sugar in the blood and make you hungry and sugar craving. Many women experience in their luteal phase a craving for sweets.


1. Vassen L et al. Human Insulin receptor substrate 2 (IRS-2) is a primary progesterone response gene. Mol Endocrinol 1999; 13:485-94


Bent Formby, PhD.  5/24/05




Osteopontin, calcium stone formation in the kidneys and high doses of progesterone 


Osteopontin is an acidic member of a small integrin-binding family of matrix proteins, which are the products of five genes clustered along the human chromosome 4. In general, osteopontin undergoes extensive posttranslational modifications believed to be important for its function. Osteopontin is an adhesion protein (“a cellular glue”) found on epithelial cells and secretions from the gastrointestinal tract, kidneys, thyroid, breast, uterus, placenta, testes and immune cells. Osteopontin is a strong supporter of development of conceptus in humans (1)


Progesterone plays a pivotal roles during gestation, including preparation of the endometrium for implantation, maintenance of pregnancy and uterine quiescence. Progesterone conjugated to its receptor strongly increases the expression of the osteopontin gene as well as formation of osteopontin protein (1).


Osteopontin in phosphorylated form is found in association with dystrophic calcification including the matrix of kidney stones primary by the interaction with calcium oxalate (2).

Osteopontin also plays a crucial role in the adhesion process of calcium oxalate crystals to renal tubular cells in stone formation (3,4). In a recent study published in the prestigious Proceedings of the National Academy of Sciences (USA), Sheng reported (5) that osteopontin strongly increased the adhesion force between a carboxylate tip and a crystal face, suggesting a path toward a better understanding of kidney stone disease. Osteopontin also plays an important role in the pancreatic stone formation process (6).


It may therefore tentatively be suggested that long-term treatment with very high doses of progesterone could be involved in the process of stone formation in the kidneys. The use of very high doses of progesterone in the clinic may thus have far reaching unknown consequences on the balance between health and disease in progesterone-target tissues.


1. Johnson GA et al. Osteopontin: Roles in implantation and placentation. Biol Reprod 2003; 69:1458-71

2. Kleinman JG et al. Osteopontin and calcium stone formation. Nephron Physiol 2004; 98:43-7

3. Yasui T et al. Osteopontin regulates adhesion of calcium oxalate crystals to renal epithelial cells. Int J Urol 2002; 9:100-8

4. Wesson JA et al. Regulation of macromolecules of calcium oxalate crystal aggregation in stone formers. Urol Res 2005; (published ahead of print)

5. Sheng X et al. Adhesion at calcium oxalate crystal surfaces and the effect of urinary constituents. Proc Natl Acad Sci (US) 2005; 102:267-72

6. Nakamura M et al. Osteopontin expression in chronic pancreatitis. Pancreas 2002; 25:182-7


Bent Formby, PhD.  5/27/05


( Linette’s trip to the ER on day 21 prompted this search of the literature. Of possible interest, Linette increased her estrogen and did not have further attacks. Laurel)



Estrogen, progesterone and the renin-angiotensin-aldosterone system. 



Several women using the WP that mimics the hormonal picture seen during gestation have observed the treatment does not bring them juvenile youth, but merely introduces reproductive/endocrine confusion. Of note is the anti-estrogenic effect mediated by the relative high build-up levels of progesterone, which adversely affect several estrogen/progesterone regulated mechanisms.


The renin-angiotensin-aldosterone system (RAAS) is a series of reactions designed to regulate blood pressure. Here is shortly how it works (see also


1. When blood pressure falls lower than 100 mm Hg for the systolic, the kidneys release the enzyme renin into the blood stream.

2. Renin in the blood splits angiotensinogen into smaller pieces. One piece is angiotensin I

3. Angiotensin I, which is relative inactive, is split into pieces by angiotensin converting enzyme (ACE). One piece is angiotensin II, which is very active. Many pharmaceuticals available to reduce high blood pressure are ACE inhibitors.

4. Angiotensin II, a hormone, conjugates to its specific receptor AT1 expressed by vascular smooth muscle cells, which causes the muscular wall of small arteries (arterioles) to constrict, increasing blood pressure. Angiotensin II also stimulates the adrenals to release the hormone aldosterone, which activates the sodium pump that causes water to be retained, thus increasing blood volume and blood pressure.

5. AT1 receptors in vascular smooth muscle cells are associated with caveolae.


Here are examples of scientific studies describing the link between estrogen/progesterone and the RAAS.


Seely et al (1) in 1999 treated 15 menopausal women with 0.1 mg transdermal estrogen for 8 weeks (plasma E2 = 14.2 pg/ml). During the last 2 weeks of the study the women were treated with low doses of progesterone (plasma P = 1.2 ng/ml). It was observed that estrogen with or without progesterone substantially lowered blood pressure. Of note was a significant progesterone activation of RAAS. Thus progesterone increased the concentration of active renin 2-fold. Plasma renin enzymatic activity also increased 2-fold.


What is the mechanism(s) responsible for the progesterone activation of the RAAS system?


The AT1 receptor mentioned above mediates many biological effects of the RAAS, such as vasoconstriction, water and sodium retention, free radical release, and cell growth (2,3). Recently Nickenig et al (2) investigated at physiological concentrations the differential effects of estrogen and progesterone on AT1 receptor gene expression in human vascular smooth muscle cells. It was found that 17beta-estradiol caused down-regulation of the AT1 receptor mRNA expression to 46%, whereas progesterone led to a significant up-regulation to 201% of control. Thus the counteracting effects of estrogen and progesterone on the cardiovascular system take place at the level of AT1 receptor regulation. These findings provide a novel insight in the mechanisms of action of reproductive hormones in the vasculature. Whereas the estrogen-induced AT1 receptor down-regulation may contribute to the atheroprotective effects of estrogen, the progesterone-caused AT1 receptor overexpression may in part explain the adverse influences of progesterone on the cardiovascular system. It should be emphasized that presently it is not certain as to whether other components of the RAAS are required to propagate vascular lesion formation or AT1 receptor overexpression itself is sufficient. In my opinion a safe cycling BHRT protocol therefore must use low maintenance concentrations of estrogen and progesterone.


Do the data reported here associate women exposed to long-term high doses of progesterone, and supposedly overexpression of AT1 receptors, with the risk of cardiovascular problems?


 1. Seely E et al. Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women. Hypertension 1999; 33:1190-94

 2. Nickenig G et al. Differential effects of estrogen and progesterone on AT1 receptor gene expression in vascular smooth muscle cells. Circulation 2000; 102:1828-33

3. Griendling KK et al. Molecular biology of the rennin-angiotensin system. Circulation 1993;87-1816-28

 4. Nickenig G et al. The AT1-type angiotensin receptor in oxidative stress and atherosclerosis. Circulation 2002; 105:530-36)


Bent Formby, PhD.  5/31/05




The human kidney has the enzyme machinery to remove pregnancy surplus levels of progesterone via biosynthesis into androgens. 


The kidneys do not like too much progesterone because it conjugates with other types of their steroid hormone receptors and blocks their function. Thus progesterone has a high affinity for the aldosterone receptor (AR), which is involved in the regulation of fluid balance and blood pressure by stimulating the active reuptake of sodium. Under normal physiological circumstances progesterone serum levels are increased during the luteal phase (from 1.5 up to 8-25 ng/ml) and pregnancy (100-200 ng/ml), which beg the question; how is it possible to protect and maintain a normal aldosterone function during 100-fold excess levels of progesterone in the kidneys? The answer is that the kidneys have the capacity to produce locally steroidogenic enzymes that effectively metabolize progesterone into androgens.

Thus, the specific aim for a study published by Dr.Quinkler et al (1) was to explore the functional activity of steroidogenic enzymes expressed in human kidney and potentially involved in androgen synthesis. In the experiments pregnenolone (a precursor to progesterone) was used because it has a better solubility in water. But the enzymes metabolizing pregnenolone into androgen of course also can metabolize progesterone into androgen.

The enzyme called P450c17 is strongly expressed in kidney tissue isolated from postmenopausal women. This enzyme catalyzes steroid 17alpha-hydroxylase and 17,20-lyase activities in the biosynthesis of androgens in gonadal as well as extragonadal tissues. Cytochrome b5 is an allosteric modulator. Thus the human kidney can metabolize surplus of progesterone via 17alpha-progesterone and androstenedione into testosterone (3-5). The same enzyme metabolize pregnenolone via 17alpha-pregnenolone and DHEA into testosterone. Since a weak activity of 5alpha-reductase was also found in the kidney some testosterone can be metabolized into dihydrotestosterone (DHT).

Of note is that the parietal cells, which are known as the source of gastric secretion in the stomach, also express and produce the enzyme P45017c and has been documented to synthesize testosterone from progesterone and androstenediol from pregnenolone (6).


It can therefore tentatively be suggested that women long-term administered pregnancy dosages of progesterone may become androgenized and hence express relevant androgenic clinical symptoms.


1. Quinkler M et al. The human kidney is a progesterone-metabolizing and androgen-producing organ. J Clin Endocrinol Metab 2003; 88:2803-9


2. Auchus RJ et al. Molecular modeling of human P450c17: Insights into reaction mechanisms and effect of mutations. Mol Endocrinol 1999; 13:1169-82


3. Luu-The V et al. Type 5 17beta-hydrosteroid dehydrogenase: its role in the formation of androgens in women. Mol Cell Endocrinol 2001; 71:77-82


4. Quinkler M et al. The role of progesterone metabolism and androgen synthesis in renal blood pressure regulation. Horm Metab Res 2004; 36:381-6


5. Bumke-Vogt C et al Expression of progesterone receptor and progesterone-metabolizing enzymes in the female and male kidney. J Endocrinol 2002; 175:349-64


6. Le Goascogne C et al. Androgen biosynthesis in the stomach: expression of cytochrome P450 17 alpha-hydroxylase/17,20-lyase messenger ribonucleic acid and protein and metabolism of pregnenolone and progesterone by parietal cells of the gastric mucosa. Endocrinology 1995; 136:1744-52


Bent Formby, Ph.D..  6/14/2005



Progesterone metabolites are neuroactive steroids with hypnotic anesthetic properties. 


Millions of messages per second are executed and received among the billions of nerve cells (neurons) in the human brain. Messages are transmitted either by electrical or chemical signals just like sending a message by telephone or by letter. We shall here only focus on chemical signals, which in the brain are called neurohormones. A neurohormone conjugates to its specific receptor expressed on the surface of a synapse which then deliver the message to the neuron. For example serotonin molecules signals via serotonin receptor complexes inside a specific brain area that you are “feeling good”. If not sufficient serotonin molecules are produced to deliver a “feeling good” message you instead feel “depressed”.

GABAA-receptors are of specific interest because they are complexes with several subunits some of which mediate the sedative-hypnotic effects of benzodiazepines (1,2). Endogenous metabolites of progesterone are powerful neuroactive steroids that modulate the function of GABAA receptor by regulating the expression of the GABAA receptor subunit genes (3). Such regulation occur during pregnancy. Thus, the concentrations in the cerebral cortex and plasma of pregnenolone as well as progesterone and its neuroactive derivatives allopregnanolone increases during pregnancy, peaking around 3rd trimester, before returning to control values immediately before delivery. Neuroactive progesterone metabolites that are produced in the brain (4) and peripheral white blood cells (lymphocytes) (5) have anxiolytic, anticonvulsant and sedative-hypnotic properties (6). Neuroactive progesterone metabolites cause fatigue in pregnancy (7). As agonistic modulators of GABAA receptors neuroactive progesterone metabolites similar to benzodiazepines markedly do increase pre-REMS and induce sleep (8).


It must tentatively be suggested that when a body is exposed to 3rd trimester pregnancy levels of progesterone (WP) for much longer periods of time than that of a normal pregnancy its neurophysiology must be expected to enter a “permanent 3rd trimester pregnancy mode”. Such a situation with build-up levels of progesterone has not been reported in the biomedical literature and may rise some clinical concern because of a potential exacerbated and permanent modulated GAABA receptor function.


1. Biggio G et al. GABAA-receptor plasticity during long-term exposure and withdrawal from progesterone. Int Rev Neurobiol 2001; 46:207-41

2. 2. Mellor JR et al. Somato-synaptic variation of GABA(A) receptors in cultured murine cerebrellar granule cells: investigation of the role of the alpha6 subunit. Neuropharmacology 2000; 39:1495-513

3. Concas A et al. Physiological modulation of GABA(A) receptor plasticity by progesterone metabolites. Eur J Pharmacol 1999; 375:225-35

4. Stoffel-Wagner B. Neurosteroid metabolism in the human brain. Eur J Endocrinol 2001; 145:669-79

5. Leb C et al. Metabolism of progesterone by human lymphocytes: production of neurosteroids. J Clin Endocrinol Metab 1997; 82:4064-68

6. Gee KW et al. A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons. Crit Rev Neurobiol 1995; 9:207-27

7. Biedermann K et al. Do neuroactive steroids cause fatigue in pregnancy? Eur J Obstet Gynecol Peprod Biol 1995; 58:15-18

8. Lancel M et al. Progesterone induces sleep comparable to those of agonistic GABAA receptor modulators. Am J Physiol 1996; 271:E763-72



Bent Formby, PhD.  6/21/05