Menthol chemical inhibits angiogeneis----bad news

[tino]

to my knowledge cyproteroneacetate blocks androgenes and androgene action in two ways.it is a steroidal antiandrogen,and drops serum testosterone alongside blocking AR.I have read some studys...they say that the risk of developing gyno is not so high when using androcur in men.That sounds like,that it also blocks aromatase activyty.In the line of this vitro study about VEGF etc,i think the receptor blocking induced the aromatase problem.

But we know that people with CAIS (Complete Androgen Insensitivity Syndrome) have luxuriant scalp hair growth, despite having non-functional androgen receptors. In their specific case, having no androgen-stimulated aromatase activity (even though there's no lack of the testosterone substrate) is not a problem for the health of their scalp hair.

I am specifically interested in the LEVEL of the reduction of testosterone (T) production, when using cyproterone acetate at typical doses. I would be surprised if that level of T reduction is really all that significant. Do you have any information on that?

To the other point....yes,i think that dropping testosterone,and hence resulting aromatisation,is especially bad for hair REGROWTH.I know that testosterone keeps up serum igf-1,but i dont know for sure,if there is a testosterone modulated cellulaer metabolism in the same way.Im more sure,that missing estrogen in the cells,drops down the insulin and igf-1 RECEPTORS.

How do you feel about those people out there who are still so convinced that estrogen is a negative factor in balding? They are big believers in the use of aromatase inhibitors for the purpose of (supposedly) fighting male pattern baldness!

I dont think that using oral or topical antiandrogenes which blocks testosterone action,cant stopp hair loss in cases with a REAL androgen dependet hair loss-receptor dependet male pattern baldness,or over systemic high androgen levels.But i don t think that this will lead to much regrowth.Almost every Study about Flutamide,Androcur etc in women whith high testo levels,shows only a slower progression of hair loss,but in the majority of cases,no regrowth.

I don't know about the effect of flutamide in women, but in men, flutamide RAISES the production of testosterone, it doesn't lower it. So at least you can't blame flutamide for reducing the substrate for aromatase, unlike with cyproterone.

I can t evaluate that in men,because whith the exception of spironolactone,i have no studys.This one...or better one small study,one topical study,and one case report,do report regrowth.Another study showes a rise in endogen estrogen in men which use spironolactone orally.And the high risk of devoloping gyno under spironolactone is well known.All that speaks for a good aromatase activity in the tissues under spironolactone.If im right.....spironolactone works a little multifactorial,it inhibits skin DHT may more well than it blocks AR-or do i be mistaken?

I've seen conflicting information on whether or not spironolactone is a 5a-reductase inhibitor. I've seen one study saying that it is, and another study saying that it isn't.

To the first point.

I think we cant compare people whith congenital Syndromes ,or preapuperty castrated males whith people who develope male pattern baldness in age classes after puberty.As first,there is no need for regrowth for them.Regrowth in the line of androgenic induced hair diseases.The second point is,that in general many things run in another way,if something about decreased anabolic hormones,or their actions which are important for many functions, is congenital.I would characterize it so,that their system runs on a metabolic "save-flame".If people whith CAIS schould have normal,or increased sytem androgen levels,than this would lead to a at least normal systemic aromatisation.The endogen estrogen can interact whith the ER-beta in the skin.And Serum IGF-1,which correlates prooven whith improoved male pattern baldness and hair growth in the line of other syndromes,is also untouched,at least in CAIS People.I think CAIS is not very well investigated.A pubmed research showed me only 70 Works about CAIS in general.If i amend the search to CAIS AND health or AND bone...only very few studys come out.Some Case reports...nothing more.

To point two...i will look right.


Point three.....i think its simply very mad to inhibit Aromatase in the line of male pattern baldness.Especially the male skin needs a good estrogen balance.Yes....a real strong estrogen domination in women maybe bad for hair.I am refering to investigations of R.paus.The showed that Estrogen inhibits tgf-beta in males,and an overdose in normestrogenic women,caused hair growth inhibition.But i think womens case is absoulutly non relevant for males-especially for male pattern baldness affected males.


Point four....i had in fact women and flutamide as idea.It seemes to decrease the Serum T there.An d the data from male patients are not conflicting?

http://jcem.endojournals.org/cgi/content/full/85/9/3251

 

[Armando Jose]

Tino wrote:

"A pubmed research showed me only 70 Works about CAIS in general.If i amend the search to CAIS AND health or AND bone...only very few studys come out.Some Case reports...nothing more."

Good point Tino, I am with you, CAIS is very little investigated and the few studies regarding CAIS and HAIR appears the word "NOVEL".By now are only conjecture, the reality is more complex than Bryan say: "Persons with CAIS have luxuriant hairs"

A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred.
J Clin Endocrinol Metab. 1999 May;84(5):1590-4.
PMID: 10323385 [PubMed - indexed for MEDLINE]

Complete androgen insensitivity syndrome caused by a novel mutation in the ligand-binding domain of the androgen receptor: functional characterization.
J Clin Endocrinol Metab. 2002 Sep;87(9):4378-82.
PMID: 12213902 [PubMed - indexed for MEDLINE]

Extreme androgen resistance in a kindred with a novel insertion/deletion mutation in exon 5 of the androgen receptor gene.
J Hum Genet. 2003;48(7):346-51. Epub 2003 Jun 7.
PMID: 12908100 [PubMed - indexed for MEDLINE]

 

[Bryan]

Point four....i had in fact women and flutamide as idea.It seemes to decrease the Serum T there.An d the data from male patients are not conflicting?

http://jcem.endojournals.org/cgi/content/full/85/9/3251

The data from male patients ARE conflicting, and it shows how unfamiliar I am with female physiology with regard to male hormone production. Apparently, females don't have a negative-feedback control of androgen production, like males do. If there's any feedback control at all, it must be POSITIVE-feedback, not negative-feedback.

 

[tino]

Point four....i had in fact women and flutamide as idea.It seemes to decrease the Serum T there.An d the data from male patients are not conflicting?

http://jcem.endojournals.org/cgi/content/full/85/9/3251

The data from male patients ARE conflicting, and it shows how unfamiliar I am with female physiology with regard to male hormone production. Apparently, females don't have a negative-feedback control of androgen production, like males do. If there's any feedback control at all, it must be POSITIVE-feedback, not negative-feedback.

a relative low dose caused a so called signifikant reduction p.05

http://www.ncbi.nlm.nih.gov/sites/entre ... stractPlus


they talk about a not clear designated moderate surpression



http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum


whitout dosage specific details.The problem is,that i dont have the full papers of such old studys.

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum



100 mg-level specific data inclusive


http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum



level specific data there,but no dosage.Isuppose that they worked whith higher dosages,because they treated prostatacancer patients.


http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum


for this indication they use ex 200 mg day here in germany.In some special cases up to 400 mg


http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum



im also not especially versed in androgen feedback reactions.But i think differnces in reactions to medical antiandrogen tratments in the same gender,can may happen due a possible extern feedback reaction,for example like its assumed in fathers,it s assumed there,because the testosterone declines when they are married.

 

[Bryan]

Ok, thanks for finding those abstracts. I seemed to recall (vaguely) that flutamide at standard doses increased testosterone levels by about 50% or so in men, but I was afraid to trust my memory!

It's still puzzling to me why it LOWERS testosterone in women, though. Apparently there just isn't a similar feedback mechanism for androgen control in women, like there is in men.

 

[tino]

citation;It's still puzzling to me why it LOWERS testosterone in women, though. Apparently there just isn't a similar feedback mechanism for androgen control in women, like there is in men.


Flutamid has mostly been tested in Women whith hyperandrogenism.I had something in my memory too,but also me was afraid to trust my memory If i remember right,than the feedback mechanisms of hyperandrogenetic women,turns other ways than the feedback loops of normandrogenic women.Im not sure,but i mean that i remember week on Studys about Flutamide and Women whith idiopathic hirsutism.They were also normandrogen,and there was no decrease in Serum Androgenes.In such cases the feedback loops could be kind of identic whith mens reaction,or in other words not so abberant from the normal difference.

We can not really find out if a systemic androgen deprivation,or blocking of AR whith the exception of Androcur,inhibits growth releated factors sytsmic or local in men.Prostatacancer Studys are irrelevand,because no one ivestigated their hair.The only Facts we have,is the certainty that Antiandrogenes like Flutamide,faild to induce significant regrowth in hyperandrogen women.Even there was the time of investigation to short.Most Studys were only made one year.And about topical AR blocking in normandrogen individuals-we have Studys about,Fluridil and spironolactone.If i do not mistake,than Fluridil induced no wonder,rather slowing of progression.spironolactone could be an exception.It lowers testosterone not so strong like for example androcur.And the AR binding capacity in vivo,is to my knowledge lower than the binding capacity of Cyproteroneacetate or Flutamide(i know the hershberger vitro storys).Although it has strong potential to induce gyno,and decrease hirsutism and Acne.It seems to work more skin specific.This could be due Tissue DHT inhibition.And last but not least,it may work over other non androgenic pathways too.

http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum

More Facts....This Finasteride/Cyproteroneacetate/VEGF Vitro Study is convenient whith the Facts that systemic 5-a-R inhibition can induce significant regrowth.We have this evidence for Finasteride,for Dutasteride,Board case reports,and a very interesting published case Report about a woman. http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum


considering other facts,i think we can not negate that Androcur does inhibit testosterone also in Vivo,in many healty normandrogen males of many age classes.

 

[phish]

so michael barry no peppermint oil?

 

[tino]

Re: addition

http://eje-online.org/cgi/reprint/141/4/361

Here Flutamide induced no significant Testosterone inhibition in normandrogen and hyperandrogen women.In this study it was compared versus Finasteride.Flutamide induced a better decrease in Hirsutism score.Finasterid worked weeker.The investigators assumed that this could also be due a effect modulated due the testosterone rising.

Androgen induced Hirsutism results from the same intracellulaer metabolic pathways than hair follicle miniaturisation.Only contrariwise.Maybe the higher Testosteron due 5-a-r inhibition,together whith non blocked AR,made the same like the Finasteride in the VHGF Vitro Study in a reversed way?

I know,about this idea there is a kind of conflict whith new findings about genetic 5-alpha-reductase activity and Hirsutism.

 

[tino]

Ok, thanks for finding those abstracts. I seemed to recall (vaguely) that flutamide at standard doses increased testosterone levels by about 50% or so in men, but I was afraid to trust my memory!

It's still puzzling to me why it LOWERS testosterone in women, though. Apparently there just isn't a similar feedback mechanism for androgen control in women, like there is in men.

this work i mean.


http://humrep.oxfordjournals.org/cgi/re ... ccef400dcb

 

[michael barry]

Phish,


Peppermint oil has to be used in pretty concentrated doses I'd imagine for that one particular chemical therein to inhibit angiogenesis, but its beyond me to say someone using it in a mixture would have that effect without it being studied.


However, It would be a heck of alot better if it didnt.


Frustrating isn't it. Curcumin, green tea, a component of peppermint oil, licorice all should be great topical anti-androgens-----but they all do inhibit angiogenesis to some extent. It would seem that this would at least make getting RE-GROWTH kinda tough. I'd still use an anti-androgen that inhibited angiogenesis over no anti-androgen at all.



Lately Ive been thinking why not just add alot of beta sitosterol (drain a capsule) into ones shampoo and leave the lather in for a few minutes. Im piddling around with beta sis on the left side of my chin now. Might see something (or not) in a couple of months. Im nosy about testing little things myself.


I'd be interested if rose hips oil (or a tea of it with an alcoholic carrier) or a clove or a arnica-based topical (or a mix of two of the above) would be effective. I havent' seen them be considered anti-angiogenic.


spironolactone isn't anti-angiogenic, but it is kinda a pain to use twice a day.


Gonna keep trudging forward. As I said, Im nosy.

 

[Bryan]

Flutamid has mostly been tested in Women whith hyperandrogenism.I had something in my memory too,but also me was afraid to trust my memory If i remember right,than the feedback mechanisms of hyperandrogenetic women,turns other ways than the feedback loops of normandrogenic women.Im not sure,but i mean that i remember week on Studys about Flutamide and Women whith idiopathic hirsutism.They were also normandrogen,and there was no decrease in Serum Androgenes.In such cases the feedback loops could be kind of identic whith mens reaction,or in other words not so abberant from the normal difference.

Well, the normal male response to flutamide is to INCREASE the production of testosterone.

 

[Bryan]

Ok, thanks for finding those abstracts. I seemed to recall (vaguely) that flutamide at standard doses increased testosterone levels by about 50% or so in men, but I was afraid to trust my memory!

It's still puzzling to me why it LOWERS testosterone in women, though. Apparently there just isn't a similar feedback mechanism for androgen control in women, like there is in men.

this work i mean.

http://humrep.oxfordjournals.org/cgi/re ... ccef400dcb

The link doesn't work.

 

[Old Baldy]

Ok, thanks for finding those abstracts. I seemed to recall (vaguely) that flutamide at standard doses increased testosterone levels by about 50% or so in men, but I was afraid to trust my memory!

It's still puzzling to me why it LOWERS testosterone in women, though. Apparently there just isn't a similar feedback mechanism for androgen control in women, like there is in men.

Bryan: You must be getting older!!?? :mrgreen:

You pointed out this (Medscape) article a while back when I asked why women don't seem to have increases in various hormones when taking medications designed to increase or limit certain androgens. The general concensus among the pros was there is no feedback mechanism in women.

Go down a few paragraphs and they state their general opinion on feedback mechanisms in women.

http://www.medscape.com/viewarticle/416448

Da**, I can't get the link to work for you guys. Here's the pertinent paragraph. (The footnote it refers to was a study done by Rittmaster in the late 1990's looking at androgen production, etc., in women.)

Ovaries and adrenals produce androstenedione, testosterone, and DHEA; adrenals also produce DHEA-S. DHEA and DHEA-S are converted peripherally into estradiol and the androgens androstenedione, testosterone, and DHT. At this consensus conference, the experts agreed that there was no direct regulator of androgen production in women (no direct stimulator or feedback mechanism). Rather, androgen production is increased by increased ovarian activity (such as that which follows increased LH secretion) or by increased adrenal activity that follows increased ACTH secretion.[2]

The article doesn't explain the reasons for this feedback difference between men and women. You know, what is genetically responsible for this difference? The article doesn't explain "why".

I don't know, is it something in our testes that does this? Is it genetic? Is it our DNA? I have no idea. But it does seem to "explain" why women can respond better to androgen treatments sometimes?

 

[Bryan]

Bryan: You must be getting older!!?? :mrgreen:

You pointed out this (Medscape) article a while back when I asked why women don't seem to have increases in various hormones when taking medications designed to increase or limit certain androgens. The general concensus among the pros was there is no feedback mechanism in women.

I have no recollection whatsoever of ever pointing out any Medscape article on that topic. Are you sure it wasn't somebody else who did that, and not me?

Da**, I can't get the link to work for you guys. Here's the pertinent paragraph. (The footnote it refers to was a study done by Rittmaster in the late 1990's looking at androgen production, etc., in women.)

Ovaries and adrenals produce androstenedione, testosterone, and DHEA; adrenals also produce DHEA-S. DHEA and DHEA-S are converted peripherally into estradiol and the androgens androstenedione, testosterone, and DHT. At this consensus conference, the experts agreed that there was no direct regulator of androgen production in women (no direct stimulator or feedback mechanism). Rather, androgen production is increased by increased ovarian activity (such as that which follows increased LH secretion) or by increased adrenal activity that follows increased ACTH secretion.[2]

Well, what's starting to really interest me now is that increased LH apparently _does_ cause increased androgen production (via the ovaries). Since those same authors are claiming that there is no direct regulator of androgen production in women (no direct stimulator or feedback mechanism), that seems to suggest that the specific thing that women are lacking is any kind of gonadotropin response (increased LH) to a decline in androgens.

The article doesn't explain the reasons for this feedback difference between men and women. You know, what is genetically responsible for this difference? The article doesn't explain "why".

Yeah, thanks for posting that, OB! I'm more than a little surprised that all this is (apparently) relatively new information. Docs have been studying endocrinology all these decades, and only in the late 1990's did they finally reach some sort of consensus about an (apparent) lack of any feedback control of androgen production in women??

I don't know, is it something in our testes that does this? Is it genetic? Is it our DNA? I have no idea.

It's the total SYSTEM in males which controls that: the cooperation between our brains and testes. The brain "sees" declining levels of androgens in our bloodstream, so it releases gonadotropins (LH and FSH) into the blood which travel to the testes to signal them to start making more testosterone (I'm glossing-over some details). So yeah, you can say that that's programmed into our DNA.

But it does seem to "explain" why women can respond better to androgen treatments sometimes?

Yeah, I guess so. If they don't have to fight the automatic feedback responses that they would ordinarily get by using androgens (or antiandrogens), that ought to require fewer resources.

 

[tino]

Ok, thanks for finding those abstracts. I seemed to recall (vaguely) that flutamide at standard doses increased testosterone levels by about 50% or so in men, but I was afraid to trust my memory!

It's still puzzling to me why it LOWERS testosterone in women, though. Apparently there just isn't a similar feedback mechanism for androgen control in women, like there is in men.

this work i mean.

http://humrep.oxfordjournals.org/cgi/re ... ccef400dcb

The link doesn't work.

how can i upload pdf files here?

 

[tino]

Re: fulltext

I copyed it out,because i cant find a mechanism to upload files here.


Human Reproduction vol.8 no.ll pp.1807-1812, 1993
The effect of flutamide on pulsatile gonadotrophin
secretion in hyperandrogenaemic women
T.Sir-Petermann1, B.Rabenbauer and L.Wildt
Division of Gynaecological Endocrinology and Reproductive
Medicine, Department of Obstetrics and Gynaecology, University
of Erlangen, Erlangen, Germany
'To whom correspondence should be addressed at: Instituto de
Investigapiones Materno Infantil, Facultad de Medicina, Universidad
de Chile, PO Box 226-3, Santiago, Chile
The pulsatile gonadotrophin secretion in hyperandrogenaemic
women was examined, following short-term androgen
antagonism induced by flutamide, a specific androgen
receptor blocker. Flutamide was administered to seven
hyperandrogenaemic women and five normal cycling women,
at a dose of 250 mg on the evening of day 1, followed by daily
doses of 750 mg for 6 days. Blood samples were collected at
10 min intervals for 8 h before (day 1) and during treatment
(days 2 and 6). Gonadotrophin and prolactin concentrations
were measured in all samples while sex hormone concentrations
were analysed in selected samples. Flutamide administration
to hyperandrogenaemic women was followed by a decrease
in luteinizing hormone (LH) pulse amplitude (P < 0.05),
associated with an apparent decline in mean LH concentrations.
Follicle stimulating hormone (FSH) showed a significant
fall after 6 days of treatment (P < 0.05). Total testosterone,
free testosterone, androstenedione and dihydroepiandrosterone
sulphate were significantly decreased during flutamide
administration, while sex-hormone-binding globulin and
oestradiol were not affected. Normal women showed no
significant changes in the above mentioned parameters. These
results demonstrate that short-term androgen receptor
blockade with flutamide reduces gonadotrophin secretion and
androgen concentration in hyperandrogenaemic women.
Since flutamide is devoid of intrinsic hormonal activity, it is
suggested that the observed hormonal changes are secondary
to the androgen blockade.
Key words: anti-androgens/flutamide/gonadotrophin pulsatility/
hyperandrogenaemia
Introduction
The effects of androgens on gonadotrophin secretion in women
are not completely understood. It has been proposed that
hypersecretion of androgens either directly or as a consequence of
the aromatizauon of oestrogens causes the abnormal gonadotrophin
dynamics which characterize the syndrome of hyperandrogenism
(Rebarer al., 1976; Yen, 1980). Most studies, however, support
the concept uiat testosterone inhibits the hypothalamic-pituitary
axis without its prior conversion to oestradiol (Santen, 1975;
Marynick et al., 1979). It has been demonstrated that luteinizing
hormone (LH) pulse frequency is reduced by testosterone
(Veldhuis et al., 1984; Urban et al., 1988). Since LH pulse
frequency is a good indicator of secretion of gonadotrophinreleasing
hormone (GnRH) from the hypothalamus (Knobil,
1980; Leyendecker et al., 1983), it has been assumed that the
effect of testosterone is exerted on the GnRH pulse generator
(Veldhuis et al., 1984). More recendy, this assumption has been
challenged by the suggestion that testosterone inhibits secretion
of LH and follicle stimulating hormone (FSH) via a GnRHindependent
mechanism acting directly on the pituitary gland
(Sheckter etal., 1989).
Investigation of the effect of androgen on gonadotrophin release
in women is of interest because it has been proposed that
androgens play an important role in uie control of gonadotrophin
secretion, either directly or following their aromatization to
oestrogens, particularly in hyperandrogenaemic women (Dunaif
etal., 1984; Fleming etal., 1985; Vermesh etal., 1987). In
normal women, injection of testosterone is followed by a decrease
of the LH pulse frequency (Serafini etal., 1986), a similar
effect to that observed in normal men (Marynick et al., 1979).
However, since the administration of testosterone to normal
women for a prolonged period of time is not feasible, an
alternative strategy might involve the administration of nonsteroidal
compounds that block the negative feedback actions of
endogenous androgens by means of their binding to androgen
receptors, without acting on gonadotrophin secretion (Urban
et al., 1988). We dierefore set out to analyse the effect of a
specific anti-androgen (flutamide) on the pulsatile gonadotrophin
secretion of hyperandrogenaemic women, in order to further
elucidate the cause—effect relationship between abnormal
gonadotrophin secretion and hyperandrogenaemia.
Materials and methods
Subjects
Seven hyperandrogenaemic women (aged 18-28 years) were
selected for study from the patients attending the Unit of
Endocrinology, Department of Obstetrics and Gynaecology,
University of Erlangen, Germany. Inclusion criteria were:
chronic oligo- or amenorrhoea, hirsutism, and plasma testosterone
concentration >0.6 ng/ml or LH/FSH ratio >3.
Hirsutism was assessed by a standardized procedure and
graded according to the severity from 0 to 3 (0, no hirsutism;
1, mild; 2, moderate; 3, severe). Hyperprolactinaemia, androgensecreting
neoplasms, Cushing's syndrome and attenuated
© Oxford University Press 1807
T.Sir-Petermann, B.Rabenbauer and L.Wildt
21-hydroxylase deficiency as well as thyroid disease were
excluded by appropriate tests.
In addition, five non-hirsute regularly ovulating women (age
22—27 years) acted as the control group. None of these women
had taken oral contraceptives or other medications for at least
6 months before starting the study and serum concentrations of
androgens and gonadotrophins were within normal limits. Prior
to the study, informed consent was obtained from all subjects.
This study was approved by the local ethical committee.
Experimental design
Flutamide, kindly provided by Dr A.Griinschneder (Essex
Pharma GmbH), was orally administered to all women at a dose
of 250 mg on the evening of day 1 and 750 mg per day, divided
in three doses, from day 2 to 6. In control women as well as
in oligomenorrhoeic patients, this treatment was initiated on the
Table I
Subject
no.
Patients
1
2
3
4
5
6b
7b
Mean
SEM
. Clinical parameters in
Age Weight BMP
(years) (kg)
26
18
27
18
19
25
28
23
1.7
Controls
1
2
3
4
5
Mean
SEM
27
24
27
23
22
25
1.0
95
51
69
59
72
51
65
66
5.7
75
54
50
60
64
61
4.3
(kg/m2)
35
23
25
20
25
22
22
25
1.9
25
20
19
23
21
22
1.1
patients and control subjects
Hirsutismd
degree
2 +
3 +
2 +
1 +
3 +
2 +
1 +
-
-
-
-
-
Menstrual
status
Ameno
Ameno
Oligo
Oligo
Ameno
Ameno
Eumeno
Eumeno
Eumeno
Eumeno
Eumeno
Eumeno
c LH/FSH
ratio
5.3
3.7
4.6
3.2
4.2
1.9
0.8
3.8
0.6
0.8
1.5
0.9
0.9
0.8
1.0
0.1
Ultrasound
finding
PCO
PCO
PCO
PCO
PCO
PCO
normal
normal
normal
normal
normal
normal
aBMI = body mass index [weight (kgyheight2 (m)].
bPatients 6 and 7 had plasma testosterone concentrations >0.6 ng/ml.
cAmeno = amenorrhoeic; oligo = oligomenorrhoeic; eumeno =
eumenorrhoeic.
dScale of increasing severity 0—3.
PCO = polycystic ovaries; LH = luteinizing hormone; FSH = follicle
stimulating hormone.
fifth day of the menstrual cycle. In the amenorrhoeic women,
the treatment began whenever feasible.
For the study of pulsatile gonadotrophin secretion, blood
samples were collected over 10 min intervals for 8 h, beginning
at 0900 h on day 1 (before the initiation of flutamide treatment),
on day 2 and on day 6 of treatment, using a sampling device
that allowed the continuous withdrawal of blood through a
heparinized catheter (Bittl et al., 1988).
LH, FSH and prolactin were determined in all samples; total
testosterone, free testosterone, androstenedione, dihydroepiandrosterone
sulphate (DHEAS), 17-hydroxyprogesterone,
oestradiol and sex hormone binding globulin (SHBG) were
measured in samples 1, 24 and 48 on days 1, 2 and 6. The free
androgen index [FAI = testosterone x 100/SHBG (nmol/1)] was
calculated, as the quotient of the molar concentrations of
testosterone and SHBG.
Hormone assays
All hormone determinations were performed in duplicate by
radioimmunoassays, using commercially available kits. All samples
from an individual subject were assessed in one single assay.
Serum LH, FSH and prolactin concentrations were determined
using commercial kits (Amersham International pic, Buckinghamshire,
UK). The intra- and interassay coefficients of variation
respectively were 4.8 and 5.5% for LH; 4.3 and 7.0% for FSH;
and 4.8 and 7.4% for prolactin.
Ultrasound examination
Ovarian morphology was assessed by ultrasound examination,
performed by the full bladder technique using a 3 MHz real time
sector scanner (Sonoline SL-2), with an electronic caliper.
Polycystic ovaries were defined according to the following
criteria: several follicles lined by the ovarian capsule, dense
ovarian stroma and enlargement of the ovaries. These criteria
were similar to those described by Adams et al. (1986).
LH pulse analysis and statistical evaluation
Discrete LH pulses were identified by the computerized version
of the cluster pulse algorithm, developed by Veldhuis and Johnson
(1986). We selected a cluster configuration of 1 x 2 (one sample
for the test peak and two for the test nadir), and a t-value of
2.1/2.1 to constrain the likelihood of false positive pulse
determinations to < 5 %. For the assessment of the LH pulse
frequency, the interpulse interval was measured.
Table II. Plasma gonadotrophin concentrations,
hyperandrogenaemic women before (day 1) and
luteinizing hormone (LH) pulse
during flutamide administration
Control women
day 1 day 2 day
characteristics
(days 2 and 6)
6
and plasma prolactin (PRL)
; values are mean ± SEM
Hyperandrogenaemic
day 1
concentration
women
day 2
in control and
day 6
LH (mlU/ml)
Pulse amplitude (mlU/ml)
Pulse interval (min)
FSH (mlU/ml)
PRL (ng/ml)
5.1 ± 0.6
1.3 ± 0.2
66 ±5
5.1 ± 0.3
6.9 ± 0.9
5.5
1.5
73
4.8
7.2
± 0.8
± 0.4
± 15
± 0.6
± 1.1
5.1
1.3
72
3.8
8.3
± 1.2
± 0.3
± 19
± 0.1
± 1.6
13.5
4.7
70
4.2
7.2
± 3.2
± 0.8a
± 8
± 0.7
± 1.2
11.4 ± 2.5
4.1 ± 1.1
76 ± 11
4.4 ± 0.7
6.3 ± 0.9
10.1
3.5
67
3.1
7.6
± 2.5
± 0.6b
± 3
± 0.6b
± 1.2
aP < 0.05 for difference between hyperandrogenaemic and control women on corresponding day.
bP < 0.05 for difference between day 6 and day 1 in hyperandrogenaemic women.
FSH = follicle stimulating hormone.
1808
Flutamide and gonadotrophin pulsatility
The LH pulse amplitude and interpulse interval, determined
by the cluster analysis, were evaluated by analysis of variance
(ANOVA) followed by Newman—Keul's multiple range tests.
Differences between day 1 and day 6 were sought by paired twotailed
Student's r-test. Results are presented as mean ± SEM.
Results
Table I shows the clinical characteristics and ultrasound findings
for the hyperandrogenaemic women compared to the controls.
The mean age of the two groups was not significantly different.
The body mass index (BMI) was similar in both groups. As
expected, the mean LH/FSH ratio was significantly higher
(P < 0.05) in the hyperandrogenaemic women compared to
the control group.
Pattern of gonadotrophin release
Prior to flutamide administration, LH pulse amplitude was
significantly higher in the hyperandrogenaemic women compared
to controls (P < 0.05), whereas LH pulse frequency was
not significantly different (Table II).
Treatment with flutamide in hyperandrogenaemic patients
resulted in a decrease in LH pulse amplitude (P < 0.05). This
became apparent within 24 h of flutamide administration,
and it was associated with a decline of mean plasma LH
concentration (not significant).
The change in the LH pulse frequency did not show a uniform
pattern (Figure 1): in two patients LH pulse frequency tended
to increase (e.g. patient 7), in two it tended to decrease (e.g.
patient 5) and in three it remained unchanged (e.g. patient 1)
under flutamide treatment. Figure 1 displays the LH pulsatile
pattern of three typical examples.
PAT.1 PAT. 5 PAT. 7
0 1 2 3 k 5 t 7
0 1 J 3 K i t 7 I 0 1 2 3 t S * 7 l 0 1 I 3 k 5 6 7 S
Fig. 1. Luteinizing hormone (LH) pulsatile pattern in three hyperandrogenaemic patients (pat), before (day 1) and during (day 6) flutamide
treatment.
Table m. Steroid levels in plasma before (day 1) and during flutamide administration (day 6); values are mean ± SEM
Control women Hyperandrogenaemic women
Testosterone (ng/ml)
Free testosterone (pg/ml)
Androstenedione (ng/ml)
DHEAS (ng/ml)
Oestradiol (pg/ml)
SHBG 0*g DHT/dl)
day 1
0.42
3.5
2.4
2108
32
1.21
± 0.05a
± 0.4"
± 0.5
± 273b
± 8
± 0.3a
day 6
0.33
3.2
2.2
1277
66
1.06
± 0.06
± 0.5
± 0.6
± 270b
± 22
± 0.2
day 1
1.46
9.0
4.5
3107
81
0.57
± 0.39bc
± 1.4b'c
± 0.9°
± 369*
± 32
± 0.1b
day 6
1.07
6.2
3.3
2158
70
0.56
± 0.26"
± 1.1"
± 0.5d
± 36 ld
± 13
± 0.1
a'bValues significantly different (P < 0.05).
c-dValues significantly different (P < 0.05).
DHEAS = dihydroepiandrosterone sulphate; SHBG = sex hormone binding globulin.
1809
T.Sir-Petermann, B.Rabenbauer and L.Wildt
PAT. 1 PAT. 5 PAT. 7
c
cr
E
5
B
I
i/)
32
2L
16
8
0
(IP/JE
.3-
SHBG
/ml)
c—
3.2
2,4
1,6
0.8
0
32
• 24
—E
• "5)16
Q.
- 1 8
ti_
0
•
• 1 1-
LH FSH - k f t PRL
r SH
• X
i11
ri FrT FrAI SHBG
LH FSH FSH
PRL LH FSH
FSH
PRL
Y-^~\ 1i 11 T FrT FrAI SHBG FrT FrAI SHBG
8
6 2
Q:
to
LL
80
60
UO
20
Fig. 2. Plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), LH/FSH ratio, prolactin (PRL), total
testosterone (T), free testosterone (FrT), free androgen index (FrAI) and sex hormone binding globulin (SHBG) in three
hyperandrogenaemic patients (PAT), before (day 1) and during (day 6) flutamide treatment.
In hyperandrogenaemic women, both FSH and LH concentration
decreased with flutamide treatment (day 1-6, Table II).
However, only the decrease in serum FSH was statistically
significant. No significant changes in pulse frequency or pulse
amplitude were noted in the control group.
Neither the controls nor the hyperandrogenaemic women
showed changes in serum prolactin concentration.
Sex hormone concentrations
Basal plasma concentration of testosterone and free testosterone,
were significantly higher in hyperandrogenaemic women, as
compared to those of control subjects (P < 0.05), while total
plasma, androstenedione, DHEAS and oestradiol concentrations
were not significantly different in the two groups. SBHG
concentrations were lower in hyperandrogenaemic women,
compared to the values in the normal control group (P < 0.05)
(Table HI). Flutamide administration decreased the plasma
concentration of testosterone in five of seven patients and decreased
the plasma concentration of free testosterone, androstenedione
and DHEAS in all patients (P < 0.05). The free androgen index
(FAI) was also significantly decreased in five of seven patients
after 6 days of flutamide administration (Figure 2, lower panel).
Conversely, plasma concentrations of oestradiol and SHBG were
not uniformly or significandy modified (Table HI). Under
flutamide treatment normal women showed a slight but not
significant decrease in testosterone, free testosterone and
androstenedione concentrations. In this group, flutamide
administration induced a significant decrease in the plasma concentration
of DHEAS in two women (P < 0.05).
1810
Discussion
To our knowledge this is the first report dealing with the effect
of flutamide on pulsatile gonadotrophin secretion in hyperandrogenaemic
and normal cycling women. Flutamide blocks
androgen receptors in the central nervous system as well as in
peripheral target organs but has no measurable effects on
oestrogen, progesterone and glucocorticoid receptors (Neri et al.,
1972; Poyet and Labrie, 1985). Its administration for 6 days to
hyperandrogenaemic women produced a significant decrease in
LH pulse amplitude. This was particularly apparent in those
patients who achieved a normalization of testosterone concentration
under flutamide administration. Although it has been postulated
that the increased amplitude of LH pulses in hyperandrogenaemic
women is secondary to androgen aromatization to oestrogen, since
flutamide decreases LH pulse amplitude by directly blocking
androgen receptors, it is possible that LH pulse generation is
restricted by androgens in some hyperandrogenaemic women;
also that LH pulse amplitude is decreased when androgen
receptors are blocked by flutamide. The consequences of blocking
the androgen receptor are difficult to interpret. In some women
LH pulse frequency increased. Since LH pulse frequency reflects
closely the GnRH pulse frequency (Clarke and Cummins, 1982),
it is likely that the effect of testosterone on pulsatile LH secretion
in hyperandrogenaemic women is similar to that observed in
males, namely an inhibition of LH release by its effect on GnRH
release (Veldhuis etal., 1984). Urban et al. (1988) have demonstrated
that LH pulse frequency was increased in normal men
after flutamide administration. FSH and LH concentrations
Flutamide and gonadotrophin pulsatility
followed the same decrease pattern, which probably reflects the
changes of the pulse generator under androgen blockade, as there
is no evidence that flutamide affects oestrogen metabolism
directly.
Another possible explanation for the decrease in the LH pulse
amplitude is that testosterone exerts a direct effect over the release
of LH and FSH at the pituitary level.
In humans, testosterone has been suggested to have a direct
inhibitory effect on the pituitary gland, independently of the effect
of GnRH (Sheckter et al., 1989). It may be speculated that the
reason why oestrogens did not change under flutamide therapy
was that androgens in the range observed in normal and hyperandrogenic
women, which may have a stimulatory effect at the
pituitary level, are inhibited under flutamide therapy. This could,
in addition, explain the decrease in LH amplitude observed under
flutamide treatment. To further clarify if androgen blockade has
a direct action on the pituitary, the effect of flutamide on LH
response to exogenous GnRH should be tested.
These observations disagree with those found by Couzinet et al.
(1989), who studied another pure anti-androgen (anandron) in
normal women and a group of poly cystic ovary patients. They
did not observe any modification of the LH pulse profile and
they concluded that there was no direct androgen effect on
gonadotrophin secretion. However, although flutamide and
anandron are both anti-androgens, they differ in their chemical
composition and therefore they may have different effects.
In the present study, plasma concentration of oestradiol was
not modified during the course of flutamide administration,
suggesting that oestrogens are probably not related to the observed
changes in gonadotrophin secretion under flutamide administration.
Significant decreases in testosterone, androstenedione and
DHEAS under flutamide treatment were observed. In normal
men, the anti-androgenic property of flutamide induces an
increase in serum testosterone and gonadotrophin concentrations
(Knuth et al., 1984). This is in agreement with the view that,
in men, testosterone is the main determinant of the negative
feedback-loop (Gooren et al., 1987), while in women the antiandrogenic
property of flutamide leads to decreased testosterone
and gonadotrophin concentrations.
There are no previous studies dealing with the short-term effect
of flutamide on androgen concentrations in women. However,
flutamide significantly decreased androgen concentrations in
superovulated rats (Yun et al., 1988). Secreto et al. (1988)
reported a sharp decrease in circulating concentrations of DHT
and DHEAS after 1 month of flutamide administration to
postmenopausal patients with breast cancer. These results are
similar to the observations made in the present study.
As there is no conclusive proof of a direct flutamide action
on the ovary, we conclude that the decrease in testosterone
concentration is the consequence of a decreased stimulation of
the ovary by LH.
DHEAS was significantly decreased during the course of
flutamide administration. A similar effect has been described by
Labrie et al. (1985) in men and by Secreto et al. (1988) in
women. This suggests that flutamide is effective in inhibiting
androgen precursor biosynthesis, at the adrenal level. The
mechanism of flutamide action on adrenal androgen biosynthesis
is not completely understood. Previous reports have attributed
this effect to inhibition of adrenal 17—20 lyase (Balzano et al.,
1988). Therefore, the decrease in plasma DHEAS concentrations
reported by Labrie et al. (1985) would be the consequence of
hormone synthesis blockade rather than corticotrophic inhibition.
The effect of flutamide on the biosynthesis of adrenal androgens
may be viewed as a favourable therapeutic effect in the treatment
of adrenal-ovarian hyperandrogenaemia.
Changes in SHBG concentrations were not observed in the
present study, despite the decrease observed in the serum
concentrations of androgens. On the other hand it has been
demonstrated that SHBG is regulated by insulin (Kiddy et al.,
1992) and that flutamide does not modify insulin concentrations
(Rabenbauer etal, 1990). The lack of variation of SHBG
concentration under flutamide administration is probably a result
of the fact that insulin levels were also unchanged by flutamide.
The fact that flutamide is devoid of intrinsic hormonal activity
allowed us to conclude that the observed changes in the LH
pulsatility in women under flutamide administration are secondary
to the androgen blockade.
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Received on March 2, 1993; accepted on July 15, 1993
1812

 

[tino]

this is interesting too.


http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum

 

[tino]

you wrote;Frustrating isn't it. Curcumin, green tea, a component of peppermint oil, licorice all should be great topical anti-androgens-----but they all do inhibit angiogenesis to some extent. It would seem that this would at least make getting RE-GROWTH kinda tough. I'd still use an anti-androgen that inhibited angiogenesis over no anti-androgen at all.


As first,we must read the Studys about abgionesis inhibition by some of this substances,before we can comment this.Can you show them?

Dont you think that angiogenesis inhibition occures only in healthy cells,or cancer cells,and not in ROS induced inflammed tissues?

 

[Old Baldy]

Hmmm... you don't remember Bryan? Maybe it was Dave or Michael? Either way, I don't think I found it. Someone else did. I could swear it was you though. However, I'm getting older also you know! :shock:

Yes, it makes sense that the brain would be involved. Good point!

You know, I wonder if it was something posted by Doctor Proctor in an old alt.baldspot post?

Anyway, women just don't seem to have that feedback mechanism.

 

[Old Baldy]

Tino: I always assumed this angiogenesis you are discussing occurred (in the context you're talking about it) in "damaged" cells, not healthy cells. (And I don't put male pattern baldness follicles and their cells in the "sick, damaged" category.) I could be wrong though. I can't remember what makes me think this but it has "stuck" in my mind now for quite a while.

There was something I read about a chemical called "T4" or "TB4", or some new novel drug where this type of problem occurred. The article went on to talk about other medications that act as anti-androgens and I can only remember saying to myself "oh, that's only a problem with 'damaged', 'sick' cells, not our male pattern baldness cells".

I just can't put my finger on the specific stuff I read to make me come to that conclusion. So I could be WRONG! :blush: