Transcript Hormonal therapy in acne

F.Fatemi,MD
Isfahan university of medical
sciences
 Hormones
which contribute to the pathogenetic
lesions of acne :
 Testosterone
 DHT
(10 times more potent than test)
 DHEA-S
 progestron
 Glucocorticoids, ACTH
 Insulin and IGF-1
 GH
 CRH and other neuroendocrine regulators
 Prolactin
 Vitamin D
 lesions along the jawline and chin
new-onset adult acne
pre-menstrual acne
cystic acne with/without menstrual
irregularities and hirsutism.
1 Standard antibiotic regimens have failed
2 Menstrual control and/ or contraception
are required alongside acne therapy
3 Oral isotretinoin is inappropriate or not
available.
Spironolactone
Cyproterone acetate (CPA)
Drospirenone
Flutamide
Anti-sense siRNA oligonucleotides
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1-Spironolactone
 It
is an aldosterone antagonist (potassium sparing
diuretic), an anti-androgen and weak progestin.
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It decreases ovarian and adrenal androgen
production.
It competitively inhibits the AR at higher doses
inhibits 5 α-R activity to a lesser extent.
It is more effective in women with acne as
compared to OCPs and low dose CA.
 OCPs
and spironolactone are synergistic and
response rates can increase by 75% with the use of
this combination.

Orally, the recommended dose is 50-100 mg after food, but
many patients show the response with a lower dose of 25
mg once or twice daily.
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Side effects include breast tenderness, irregular menstrual
cycles, and electrolyte imbalance (hyperkalemia seen with
high doses) , rarely melasma , gynecomastia.
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Dietary withholding of excessive amounts of bananas and
diet soda is advised.
Periodic monitoring of serum potassium levels early in
therapy is recommended.

Contraindications:
 pregnancy (cause hypospadias in the male fetus.)
 women with risk of breast cancer (theoretical increase in
breast cancer, shown in animal but not human studies)
2- Cyproterone acetate

It is both an anti-androgen and progestin but Its anti-acne
effects are mediated primarily through androgen receptor
blockade.
The dosage ranges from 2 to 100 mg daily.
A- monotherapy 50-100mg/D effective in more than 75% of
women with acne.
B-When used singly it can be administered from day 1 to 10 of
the menstrual cycle.
C-similar efficacy reported for the 2 mg CPA dose in the Diane
D- Diane + 50-100mg/D on days 5-14 of the menstrual cycle.
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It is very effective in recalcitrant acne associated with
PCOS.
3-Drospirenone
It is a novel progestin having both anti-androgenic and
anti-mineralocorticoid activity.
 Drospirenone differs from other synthetic progestins in
that it is closer to the natural progesterone.
 As such it has potent antimineralocorticoid properties,
counteracts the estrogen-stimulated fluid retention .
 The anti mineralocorticoid properties exhibited by
drospirenone promote sodium excretion and prevent
water retention.
 In combination with lower doses of estrogen
(drospirenone 3 mg/ethinyl estradiol 20, 30 μg , Yaz®
,Yasmin®), it is reported to have a beneficial effect in
acne vulgaris, and hirsutism
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Major side effects include thromboembolic episodes,
and hyperkalemia.
contraindications:
Hepatic and renal dysfunction
 Adrenal insufficiency
 Smokers
 history of DVT, stroke, or other blood clots.
 Concomitant with drugs, which can induce dangerous
levels even fatal hyperkalemia :
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ACE inhibitors (captopril & Enalopril)
Angiotensin-II receptor agonists (Lozartan & Valzartan)
potassium-sparing diuretics (Spiranolactone)
potassium supplementation
Heparin
aldosterone antagonists
NSAIDs
A recent study, albeit small,
confirmed efficacy and good
tolerability in 27 women with
nodulocystic acne treated with
yasmin+100 mg spironolactone .
Low dose steroid
Low-dose glucocorticoids (prednisolone 2.5-5 mg daily
at bedtime) or low-dose dexamethasone is useful in
patients with late onset CAH,

Enzyme deficiency,cause steroid precursors
accumulation and are shunted into the pathway for
androgen biosynthesis.
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The risk of adrenal suppression is higher with
dexamethason
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Serum DHEAS can be monitored for evaluating the
effect of steroids. The levels of DHEAS are normalized
following treatment.
GnRH
Cocps
agonists
Combined oral contraceptives
They are combinations of an estrogen and a progestin.
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The estrogenic component is :
usually ethinyl estradiol and rarely mestranol.
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Although some progestins have androgen-like effects,
when combined with EE, the net result is overall antiandrogenic.
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Most of the combined oral contraceptives (COCs) in the
market today contain lower doses of estrogens(20-50 μg)
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They used to contain high doses of estrogen (100 μg).
Progestins
Unlike
endogenous progesterone,
synthetic progestins are 19Nortestosterone derivatives and may
cross react with the AR causing
aggravation of acne, hirsutism,
And.alopecia.
Thus
the treatment of acne necessitates
choosing an OCP that contains a
progestin with low androgenic
properties.
New low androgenic progestins:
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second-generation ,low-androgenic progestins :
Ethynodiol diacetate , norethindrone : levonorgestrel ,
Norgestrel
 Third-generation progestins :
Desogestrel, norgestimate, gestodene have even less
androgenic activity than their predecessors.
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otherS(Forth generation) progestins (drospirenone, CPA ,
dienogest ) haveantiandrogenic properties.
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Drospirenone is the only progestin which is FDA approved that
blocks the AR and is truly anti-androgenic, even without the
addition of EE .
Because of the potential risks
associated with oral contraceptive use
and the need for breast and pelvic
examinations, consultation with a
gynecologist is recommended.
Side-effects include :
 nausea, headache, breast tenderness, bloating,
breakthrough bleeding, acne, decreased sexual desire
and depression, weight gain.
 Thromboembolic episodes were much higher with COCs
having a high estrogen dose and these events have
decreased with current low estrogen formulations.
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Low-dose COCs :
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may increase the incidence of MI in women. Those
with a history of hypertension, smoking or migraine,
associated with an aura have an increased risk.
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The frequency of venous thromboembolism is also
about three times higher in COC users as compared to
non-users.
 Women
who take contraceptive pills containing
drospirenone have a six- to sevenfold risk of
developing thromboembolism compared to women
who do not take any contraceptive pill, and have
twice to thrice the risk compared to women who
take a contraceptive pill containing
levonorgestrel.
 Though the actual risk is small, in the
neighborhood of 9 to 27 out of 10,000 women on
an oral contraceptive for a year (up to 9 for
levonorgestrel vs up to 27 for drospirenone.)
 They
found that the risk of VTE, which includes
dangerous and potentially fatal blood clots, was
93% higher for women who had been taking oral
contraceptives made with drospirenone for only 3
months or less and 290% higher for women taking
drospirenone oral contraceptives for 7–12 months,
compared to women taking other types of OCPs.
 The
FDA recently updated the label for
contraceptives containing drospirenone to include
warnings for stopping use prior to and after
surgery, and to warn that contraceptives with
drospirenone may have a higher risk of dangerous
blood clots.[
In 2008, a series of television commercials
prompted the FDA to cite Bayer for overstating
the approved uses of Yaz while failing to
adequately warn viewers about the risks of the
drug.
As of August 2012, Bayer has notified its
stockholders that there are more than 12,000
lawsuits against the company involving Yaz,
Yasmin, and other oral contraceptives with
drospirenone, and the company thus far has
settled 1,977 cases for $402.6 million, for an
average of $212,000 per case, while setting aside
$610.5 million to settle the others.[10
 5-αR exists as 2 isoenzymes with different
localization.
 Type 1 isoenzyme is predominantly localized to the
sebaceous glands and also in epidermis, eccrine
sweat glands, apocrine sweat glands, hair follicles
(outer root sheath cells, dermal papilla cells, matrix
cells), endothelial cells of small vessels and in the
Schwann cells of myelinated nerves in the skin.
 Type
2 isoenzyme is localized predominantly to the
prostate and genital skin and in hair follicles in
inner layer of outer root sheaths, inner root sheaths,
infundibulum, and the sebaceous ducts.
4-azasteroid derivatives
Finasteride is a specific, competitive, type 2 5 α-R
inhibitor effective for benign prostatic hyperplasia and
androgenetic alopecia. However, there is no reduction of
sebum secretion, possibly because it does not affect the
type 1 isoenzyme in the sebaceous gland.
Dutasteride also a 4-azasteroid inhibits both the
isoenzymes. These molecules have not been found to be
effective in women. Besides dutasteride is
contraindicated in women.
Turosteride is a potent inhibitor of type 2
isoenzyme.
 Other
medications with 5 α-R inhibitor action
include zinc, azelaic acid, saw palmetto, and
various phytotherapeutic agents.
 Zinc,
inhibits the type 1 isoenzyme.
 Azelaic
 Saw
acid have dual 5 α-R inhibitor action.
palmetto berries (Serenoa repens) have dual
5 α-R inhibitor action and contain phytosterols (βsitisterol, stigmasterol, lupeol, lupenone, and
cycloartenol).
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Bromocriptine
Cabergoline and quinagolide
 Quinagolide can be used until
the point of confirmation of
pregnancy test and so is now
considered a first-line agent in the
treatment of hyperprolactinemia
Metformine
 Insulin
resistance is characterized by reduced
cellular uptake of glucose and normal or
increased levels of insulin.
 In IR, the intracellular pool of the insulinresponsive glucose transporter 4 (GLUT 4) is
markedly reduced.
Metformin, a biguanide reverses this effect
by delaying GLUT 4 endocytosis and by
increasing GLUT 4 gene expression, both
resulting in increased glucose uptake and
revering the insulin resistance.
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Serious side effects to metformin treatment are very
rare.
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It is important to note that metformin does not cause
hypoglycaemia.
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In the 1 st week, an upset stomach or diarrhea is
common and this side effect can be reduced by taking
it after food and by starting with a very low dose (250
mg), increasing slowly by 250 mg per week until the
full dose of 1500-2000 mg is achieved.
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Metformin works much better if combined with a strict
regime of diet and exercise.
 There
are no recommendations on how long to
continue the drug.
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A beneficial effect should be seen within 6
months for continuation.
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Metformin restores regular menses in
approximately 62% of predominately obese PCOS
women
A
second generation tetracycline Limecycline
The macrolide roxithromycin
have both anti-androgenic & anti-inflammatory actions
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 Ketoconazole exerts its anti-androgenic effect by 2
mechanisms.
1)High oral doses (400 mg thrice daily) blocks testicular
and adrenal androgen synthesis, decreasing serum
testosterone levels.
2)It also acts as an AR antagonist competing with
testosterone and DHT, in high oral doses.
 Vitamin
D deficiency has been reported to
aggravate :
menstrual irregularities
 insulin resistance
 Hirsutism
 HA associated with the PCOS.

 Supplementation
of vitamin D may prove beneficial
Recently the sebosuppressive effect of isotretinoin has
been explained by reduction in formation of DHT and
androstenedione as isotretinoin competitively inhibits 3
α-hydroxysteroid oxidation by retinol dehydrogenase.
Only oral regimen:In males, 25 mg CPA has
been used with success, but it reduces libido
and produces gynaecomastia and possible
azoospermia.
topical spiranolactone 5% &Topical CPA in a
novel vehicle (solid lipid nano particles)
having enhanced follicular penetration may
be useful when systemic medication is
unacceptable and can be used in both men
and women