Why Preeclampsia is Increasing: Testosterone

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James Michael Howard
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Why Preeclampsia is Increasing: Testosterone

This is intended to demonstrate that an ongoing, pathological phenomenon may be directly connected to my explanation of human evolution. That is, human evolution is directly influenced by levels of testosterone within populations. It is my hypothesis that testosterone is rising in society. More specifically, it is my hypothesis that the percentage of individuals who produce more testosterone is increasing compared to people who produce less. I suggest the increase in percentage of individuals of higher testosterone is identifiable as a change in children known as the "secular trend." The secular trend is the increase in height and weight and earlier puberty in children. (That is, children of higher testosterone are bigger and reach puberty earlier.) The secular trend is real and was recently documented in the United States (Freedman, D.S., et al., "Secular trends in height among children during 2 decades, The Bogalusa heart study," Archives of Pediatric and Adolescent Medicine 2000; 154:155-161). A secondary hypothesis suggests increased testosterone causes a number of problems within groups of higher testosterone. This may be occurring at this time. Among these problems may be an increase in a severe complication of pregnancy called preeclampsia. The Associated Press reported March 13, 2001, in: "Dangerous pregnancy complication on the rise," that preeclampsia is on the rise in the United States: "The NIH [National Institutes of Health] just sounded an alarm that the preeclampsia rate rose by nearly a third during the 1990s." The rise in the percentage of individuals of higher testosterone increases the fecundity of humans as well as specific characteristics of the hominid line. However, excessive amounts of testosterone produce characteristic negative phenomena within the hominid line and humans. This periodic cycling of high versus low levels of testosterone within populations has produced periodic shifts in hominid and human populations. Preeclampsia may be one of these negative consequences of excessive testosterone; the increase may represent a consequence of high levels of testosterone.

This may be identifiable in the effects of testosterone on an enzyme, epoxide hydrolase, associated with preeclampsia. Steegers, E.A., et al., "A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia," (Journal of Medical Genetics 2001; 38: 234-237) report a connection between genotype variability of the gene for "epoxide hydrolase" and the incidence of preeclampsia. "Microsomal epoxide hydrolase is an important enzyme involved in the metabolism of endogenous and exogenous toxicants." The "high activity genotype" occurs more often (29%) in preeclampsia than in controls (16%). They conclude that: "Women with the high activity genotype in exon 3, which could reflect differences in metabolic activation of endogenous or exogenous toxic compounds, may have enhanced susceptibility to pre-eclampsia."

Exposure to testosterone is directly involved in expression of epoxide hydrolase in the livers of adult rats (Denlinger, C.L. and Vesell, E.S., "Hormonal regulation of the developmental pattern of epoxide hydrolases. Studies in rat liver," Biochemical Pharmacology 1989 Feb 15; 38(4): 603-10). Treatment of castrated mice with testosterone increases soluble epoxide hydrolase activity between 49% and 400% depending upon the tissue examined (Pinot, F., et al., "Differential regulation of soluble epoxide hydrolase by clofibrate and sexual hormones in the liver and kidneys of mice," Biochemical Pharmacology 1995; 50(4): 501-8). Testosterone activates soluble and mitochondrial expoxide hydrolase activity, while ".estradiol treatment showed a suppressive effect on both subcellular activities in males, but had no effect on female activities." (Inoue, N., et al., "Sex hormone-related control of hepatic epoxide hydrolase activities in mice," Biological and Pharmaceutical Bulletin 1993 Oct; 16(10): 1004-7).

A number of reports connect high levels of testosterone directly to preeclampsia: "Levels of the potent androgen testosterone were significantly higher in primigravid women with preeclampsia than in normotensive women with similar gestational and maternal ages. This difference may indicate a role for testosterone in the pathogenesis of preeclampsia." (Acromite, M.T., et al., "Androgens in preeclampsia," American Journal of Obstetrics and Gynecology 1999; 180: 60-3) and. "A history of preeclampsia an average of 17 yr earlier thus appears to be associated with elevated levels of testosterone, which may contribute to the increased risk of vascular morbidity in such women." (Laivuori, H., et al., "Evidence of high circulating testosterone in women with prior preeclampsia," Journal of Clinical Endocrinology and Metabolism 1998; 83: 344-7)

It is my hypothesis that testosterone is rising in society. More specifically, it is my hypothesis that the percentage of individuals who produce more testosterone is increasing compared to people who produce less. I suggest the increase in percentage of individuals of higher testosterone is identifiable as a change in children known as the "secular trend." The secular trend is the increase in height and weight and earlier puberty in children. (That is, children of higher testosterone are bigger and reach puberty earlier.) The secular trend is real and was recently documented in the United States (Freedman, D.S., et al., "Secular trends in height among children during 2 decades, The Bogalusa heart study," Archives of Pediatric and Adolescent Medicine 2000; 154:155-161).

Preeclampsia is increasing in the United States. I suggest this increase results from an increase in the percentage of women who produce increased levels of testosterone. Increased levels of testosterone may activate the "high activity genotype" of epoxide hydrolase in women of higher testosterone. This may account for the increase in preeclampsia.

Copyright 2001, James Michael Howard, Fayetteville, Arkansas, U.S.A.

Guy Sovak
Guy Sovak's picture
Dear James Michael,

Dear James Michael,
It is a very interesting theory.
I didnt know what is Preeclampsia, so for all of thoes who didnt know follow this attachment:
http://www.preeclampsia.org/about.asp.
I have heard heories about rising of testosteron during the last decades.
I also heard about rising of testosteron and violance.
Do you have an idea or esamption how much would it rise in the next decade.
Guy

PS
It was a bit long what you wrote.
Guy

James Michael Howard
James Michael Howard's picture
guy wrote:Dear James Michael,

guy wrote:

Dear James Michael,
It is a very interesting theory.
I didnt know what is Preeclampsia, so for all of thoes who didnt know follow this attachment:
http://www.preeclampsia.org/about.asp.
I have heard heories about rising of testosteron during the last decades.
I also heard about rising of testosteron and violance.
Do you have an idea or esamption how much would it rise in the next decade.
Guy

Thank you for your question. I cannot say with certainty, however, I will say that the level of testosterone appears to be rising at a steady rate. I base this on my hypothesis that this increase is the cause of many of the increasing diseases such as obesity, breast cancer, diabetes, etc. Also, the increase in problems with education also may be caused by this increase in testosterone and education problems, especially for boys, are increasing rapidly.

Fraser Moss
Fraser Moss's picture
The site address as listed

The site address as listed above did not work for me. the one below did

http://www.preeclampsia.org/about.asp

Also - Question a to JMH. Are you purely thoeretical scientist or have to done any of your own practical work to support your theories?

Jason King
Jason King's picture
Isn't it more likely that

Isn't it more likely that diseases that are directly related to high blood pressure are increasing because of our increasingly lazy westernised lifestyle. (e.g. Supersize-me).

Average baby size is increasing because pregnant mums are no longer moving around as they used to. The result is bigger babies and more birth complications (although high blood pressure is not the most common).

The more interesting effects of varying testosterone levels in pregnant women (which are published in "Nature") relate to level of offspring fitness (post high testosterone at about week 14) and chances of male children choosing a gay lifestyle (following low testosterone).

James Michael Howard
James Michael Howard's picture
www.preeclampsia.org "In

www.preeclampsia.org "In developing countries, as many as 30 percent of maternal deaths are caused by preeclampsia..." compared to "Preeclampsia occurs in 5-8 percent of all pregnancies..." here. Sounds like "westernised" protects against preeclampsia according to www.preeclampsia.org

Fraser Moss
Fraser Moss's picture
Some more up-to-date

Some more up-to-date references for everyone to chew on before we all get too carried away on this one.

1: Salamalekis E, Bakas P, Vitoratos N, Eleptheriadis M, Creatsas G.
Androgen levels in the third trimester of pregnancy in patients with
preeclampsia.
Eur J Obstet Gynecol Reprod Biol. 2005 Aug 31; [Epub ahead of print]
PMID: 16139944 [PubMed - as supplied by publisher]

2: Carlsen SM, Romundstad P, Jacobsen G.
Early second-trimester maternal hyperandrogenemia and subsequent preeclampsia:
a prospective study.
Acta Obstet Gynecol Scand. 2005 Feb;84(2):117-21.
PMID: 15683369 [PubMed - indexed for MEDLINE]

3: Atamer Y, Erden AC, Demir B, Kocyigit Y, Atamer A.
The relationship between plasma levels of leptin and androgen in healthy and
preeclamptic pregnant women.
Acta Obstet Gynecol Scand. 2004 May;83(5):425-30.
PMID: 15059152 [PubMed - indexed for MEDLINE]

4: Baksu A, Gurarslan H, Goker N.
Androgen levels in pre-eclamptic pregnant women.
Int J Gynaecol Obstet. 2004 Mar;84(3):247-8. No abstract available.
PMID: 15001373 [PubMed - indexed for MEDLINE]

5: Troisi R, Potischman N, Johnson CN, Roberts JM, Lykins D, Harger G, Markovic
N, Siiteri P, Hoover RN.
Estrogen and androgen concentrations are not lower in the umbilical cord serum
of pre-eclamptic pregnancies.
Cancer Epidemiol Biomarkers Prev. 2003 Nov;12(11 Pt 1):1268-70.
PMID: 14652293 [PubMed - indexed for MEDLINE]

6: Troisi R, Potischman N, Roberts J, Siiteri P, Daftary A, Sims C, Hoover RN.
Associations of maternal and umbilical cord hormone concentrations with
maternal, gestational and neonatal factors (United States).
Cancer Causes Control. 2003 May;14(4):347-55.
PMID: 12846366 [PubMed - indexed for MEDLINE]

7: Takanashi K.
[Studies on 2-hydroxyestradiol 17-sulfate derived from fetoplacental unit: the
antioxidant as a potential defense substance against preeclampsia]
Yakugaku Zasshi. 2003 Jun;123(6):399-411. Review. Japanese.
PMID: 12822484 [PubMed - indexed for MEDLINE]

8: Seely EW, Solomon CG.
Insulin resistance and its potential role in pregnancy-induced hypertension.
J Clin Endocrinol Metab. 2003 Jun;88(6):2393-8. Review.
PMID: 12788833 [PubMed - indexed for MEDLINE]

9: Troisi R, Potischman N, Roberts JM, Ness R, Crombleholme W, Lykins D,
Siiteri P, Hoover RN.
Maternal serum oestrogen and androgen concentrations in preeclamptic and
uncomplicated pregnancies.
Int J Epidemiol. 2003 Jun;32(3):455-60.
PMID: 12777436 [PubMed - indexed for MEDLINE]

10: Miller NR, Garry D, Cohen HW, Figueroa R.
Serum androgen markers in preeclampsia.
J Reprod Med. 2003 Apr;48(4):225-9.
PMID: 12746983 [PubMed - indexed for MEDLINE]

11: Ficicioglu C, Kutlu T.
The role of androgens in the aetiology and pathology of pre-eclampsia.
J Obstet Gynaecol. 2003 Mar;23(2):134-7.
PMID: 12745554 [PubMed - indexed for MEDLINE]

12: Jirecek S, Joura EA, Tempfer C, Knofler M, Husslein P, Zeisler H.
Elevated serum concentrations of androgens in women with pregnancy-induced
hypertension.
Wien Klin Wochenschr. 2003 Mar 31;115(5-6):162-6.
PMID: 12741075 [PubMed - indexed for MEDLINE]

13: James WH.
Hormone levels in pre-eclampsia.
Acta Obstet Gynecol Scand. 2002 Dec;81(12):1152; author reply 1152. No abstract
available.
PMID: 12519112 [PubMed - indexed for MEDLINE]

14: Wolf M, Sandler L, Jimenez-Kimble R, Shah A, Ecker JL, Thadhani R.
Insulin resistance but not inflammation is associated with gestational
hypertension.
Hypertension. 2002 Dec;40(6):886-91.
PMID: 12468574 [PubMed - indexed for MEDLINE]

15: Lubin V, Gautier JF, Antoine JM, Beressi JP, Vexiau P.
[Cushing's syndrome during pregnancy]
Presse Med. 2002 Nov 9;31(36):1706-13. Review. French.
PMID: 12467153 [PubMed - indexed for MEDLINE]

16: Steier JA, Ulstein M, Myking OL.
Human chorionic gonadotropin and testosterone in normal and preeclamptic
pregnancies in relation to fetal sex.
Obstet Gynecol. 2002 Sep;100(3):552-6.
PMID: 12220777 [PubMed - indexed for MEDLINE]

17: Serin IS, Kula M, Basbug M, Unluhizarci K, Gucer S, Tayyar M.
Androgen levels of preeclamptic patients in the third trimester of pregnancy
and six weeks after delivery.
Acta Obstet Gynecol Scand. 2001 Nov;80(11):1009-13.
PMID: 11703197 [PubMed - indexed for MEDLINE]

18: Casart YC, Camejo MI, Proverbio F, Febres F.
Bioactivity of serum hCG in preeclampsia.
Obstet Gynecol. 2001 Sep;98(3):463-5.
PMID: 11530130 [PubMed - indexed for MEDLINE]

James Michael Howard
James Michael Howard's picture
Thank you for the list. Now,

Thank you for the list. Now, why don't you digest them for us. Thanks.

Fraser Moss
Fraser Moss's picture
I would have thought you

I would have thought you would be extremely interested in digesting them yourself too. This is your speciality and you appear very keen to post your theories about testosterone and its relation to many syndromes in many places on the web and in letters to scientific journals.

**POST EDITED SINCE ORIGINAL**
I have scanned through them all now. In a very small nut-shell, of the references I listed above that directly addressed the question of the relation of maternal serum androgen/testosterone levels to preeclampsia there appeared to be an almost 78% are on favour of peeclampsic women having elevated Testosterone and other androgens realtive to normotensive subjects and that this could be used as an early idicator for preeclampsia detection.

FOR

"The levels of total and free testosterone appear to be higher in patients with preeclampsia compared to normotensive pregnant women during the third trimester of pregnancy. This difference could indicate an involvement of testosterone in the pathophysiology of preeclampsia and stimulates research in the potential role of anti-androgens in the management of preeclampsia."

Salamalekis Eur J Obstet Gynecol Reprod Biol. 2005 Aug 31; [Epub ahead of print]

"Maternal androgen levels are already elevated in the early second trimester among women who eventually develop preeclampsia. Thus hyperandrogenism may be considered as an early risk marker of preeclampsia and it might be involved in the pathogenesis of preeclampsia."
Carlsen et al Acta Obstet Gynecol Scand. 2005 Feb;84(2):117-21.

"We concluded that the elevated plasma levels of leptin and testosterone could contribute to the endothelial dysfunction involved in the pathogenesis of preeclampsia, and that estradiol might lead to an increase in the plasma levels of leptin"

Atamer Y Acta Obstet Gynecol Scand. 2004 May;83(5):425-30.

"Women with pregnancy-induced hypertension have elevated serum concentrations of androstenedione and testosterone. Moreover, elevated serum concentrations of androstenedione are associated with development of severe disease."
Jirecek S et al Wien Klin Wochenschr. 2003 Mar 31;115(5-6):162-6.

"Serum unconjugated oestradiol, oestrone, and oestriol concentrations were not lower in preeclamptic pregnancies in a matched analysis with adjustment for race and whether blood was collected before or after labour commenced. Serum unconjugated androstenedione (506.3 versus 316.0 ng/dl; P = 0.0007) and testosterone concentrations (214.5 versus 141.9 ng/dl; P = 0.004), however, were significantly higher in preeclamptic compared with control pregnancies, whereas dehydroepiandrosterone (DHEA) and DHEA sulphate did not differ.."
Troisi et al Int J Epidemiol. 2003 Jun;32(3):455-60.

"In preeclamptic pregnancies with male fetuses, the maternal serum Human chorionic gonadotropin levels were significantly higher than in uncomplicated pregnancies. Total testosterone levels were significantly higher in pregnancies with either gender and significantly higher in male-bearing than in female-bearing pregnancies. This may indicate an androgen influence on the pathophysiologic mechanism of preeclampsia."
Steier JA et al Obstet Gynecol. 2002 Sep;100(3):552-6.

"We conclude that higher blood androgen levels measured in preeclamptic patients may be implicated in the pathogenesis of preeclampsia."
Serin IS et al, Acta Obstet Gynecol Scand. 2001 Nov;80(11):1009-13.

Against

"Maternal serum levels of androgens do not exhibit an association with preeclampsia in primigravid women."
Miller NR et al J Reprod Med. 2003 Apr;48(4):225-9.

"We reached the opinion that androgens do not play a clinically significant role in the pathogenesis of pre-eclampsia."
Ficicioglu C & Kutlu T. J Obstet Gynaecol. 2003 Mar;23(2):134-7.

So the recent evidence does appear to be trending towards a link between elevated testosterone and incidence of preeclampsia. I think at ths stage, however, we cannot make the leap that this is because of an increase in testosterone levels in society (which itself has many potential parameters - western? eatsern, northern hemishere? Southern hemisphere?, Africa, Asia, Europe, North America? Urban? Rural?) that is directly influencing incidence of conditions like preeclampsia and HIV/AIDS in Africa as discussed by JMH in a couple of topics, without performing direct controlled studies of various populatoins or citing literature that has already done so (this may be out there, but this is not at all my speciality so I cant say). Furthermore, there are many other environmental factors as well as physiological factors that will influence hormone levels and disease incidence. Also, in the case of preeclamsia, from the very little I read, I'm not sure that increased testostrone levels are causal or an indicator of the condition onset, or both. Further research into this is obviously continuing.

James Michael Howard
James Michael Howard's picture
Thank you, frasermoss, for

Thank you, frasermoss, for your interpretation. I guess all I can say is that the literature appears to be swinging towards an involvement of testosterone in preeclampsia with time.

Guy Sovak
Guy Sovak's picture
A very interesting debate I

A very interesting debate I must say.
50/50 means that there is no assurance that one is right and the other is wrong.
I just want to emphasize two things:
First of all the Theory about Gay lifestyle and testosterone levels in the mother through pregnancy. Lots was said about it long time ago, since the end of the last decade the number of articles in that topic have declined dramaticaly, what does it say to us?????
Second: I really think that this is not the place to post theories.
Guy

James Michael Howard
James Michael Howard's picture
As you wish; I will not post

As you wish; I will not post any more "theories," nor will I respond to any more responses for the same reason.

Guy Sovak
Guy Sovak's picture
It seems that you are

It seems that you are offended somehow.
If so I am sorry.
Every member here is very important.

Sandy
Sandy's picture
James Michael Howard wrote

James Michael Howard wrote:

Thank you, frasermoss, for your interpretation. I guess all I can say is that the literature appears to be swinging towards an involvement of testosterone in preeclampsia with time.

Dear Dr. Howard,

I have been occasionally reading your postings and your opinion about different disorders even infectious diseases(AIDS) being caused by elevated levels of testosterone. It is very bizarre theory to understand and to prove as well. If higher levels of male hormone are the cause for so many different problems in advanced societies, may be we can blame the pollution. Otherwise, may be we should leave it alone because it could be a sign of natural selection. May be in about one million years from now a new human being will dominate the planet who cannot be affected by high levels of testosterone?

JMore
JMore's picture
I have to completely disagree

I have to completely disagree with this.

Research is suggesting that preeclampsia may not be so black and white. With the new research regarding levels of S-flt and sEng (higher levels of both, but more s-flt in PE patients and more sEng in HELLP patients) testosterone may play a slight role, but it is certainly not the astonomical connection you are trying to make it out to be.

I'll use myself as an example :

white 21 year old female- physically fit (5'3" 93lbs and active) no history of underlying disorders or hypertension in my family.

I was on spironolactone at age 14 for mild acne. Side effect was amenorrhea. dermatologist gave an oral contraceptive to start menstrual flow.

at age 20 decided I did not want to be on oral contraceptives and went off. stayed on spironolactone. Amenorrhea returned.

7 months later went to an OB and was instucted to stop spironolactone and take 5 days of progesterone to start mentrual cycle. Mentration never returned, but I found out two weeks later I was expecting a child.

Spironolactone is a testosterone antagonist (as well as aldosterone) and the reason that I had amenorrhea was because I had little testosterone production to begin with.

I got severe preeclampsia and HELLP syndrome at 34 weeks.

No testosterone problems. However there may be a link between low levels of aldosterone and preeclamptic patients.