F.Fatemi,MDIsfahan 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 chinnew-onset adult acnepre-menstrual acnecystic 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)DrospirenoneFlutamideAnti-sense siRNA oligonucleotides

1-Spironolactone

It is an aldosterone antagonist (potassium sparing diuretic), an anti-androgen and weak progestin. 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.

Side effects include breast tenderness, irregular menstrual cycles, and electrolyte imbalance (hyperkalemia seen with high doses) , rarely melasma , gynecomastia.

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.

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

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 : 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.

The risk of adrenal suppression is higher with

dexamethason

Serum DHEAS can be monitored for evaluating the effect of steroids. The levels of DHEAS are normalized following treatment.

GnRH agonists Cocps

Combined oral contraceptives They are combinations of an estrogen and a progestin.

The estrogenic component is : usually ethinyl estradiol and rarely mestranol.

Although some progestins have androgen-like effects, when combined with EE, the net result is overall anti-androgenic.

Most of the combined oral contraceptives (COCs) in the market today contain lower doses of estrogens(20-50 μg)

They used to contain high doses of estrogen (100 μg).

Progestins Unlike endogenous progesterone,

synthetic progestins are 19-Nortestosterone 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: second-generation ,low-androgenic progestins

:

Ethynodiol diacetate , norethindrone : levonorgestrel , Norgestrel

Third-generation progestins :

Desogestrel, norgestimate, gestodene have even less

androgenic activity than their predecessors.

otherS(Forth generation) progestins (drospirenone, CPA , dienogest ) haveantiandrogenic properties.

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.

Low-dose COCs : 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.

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 acid have dual 5 α-R inhibitor action.

Saw palmetto berries (Serenoa repens) have dual 5 α-R inhibitor action and contain phytosterols (β-sitisterol, stigmasterol, lupeol, lupenone, and cycloartenol).

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 insulin-responsive 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.

Serious side effects to metformin treatment are very rare.

It is important to note that metformin does not cause hypoglycaemia.

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.

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.

A beneficial effect should be seen within 6 months for continuation.

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

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 resistanceHirsutismHA 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