Acne in women: a manifestation of hyperandrogenism. How to treat it? – Dr. C. Jamin

Acne is a multifactorial dermatosis whose hormonal dependence is indisputable and whose treatment in women is currently often hormonal therapy. The new heavy constraints on the third and fourth generation oestrogen-progesterone pills will very likely change how acne is treated in women.

The appearance of acne coincides with the start of the gonadal function. Almost all teenagers get acne, which improves with time in most, but which can continue into adulthood.

Hormones and acne

The functioning of the sebaceous gland depends on gonadal secretions and the improvement of acne lesions over time can be related to an (unexplained) process of desensitisation over time of hormone receptors, fairly classic in hormonology. Sebum production under the influence of androgens is very important at the beginning of hormonal impregnation, then it decreases due to this desensitisation of the sebaceous gland to androgens with age. The use of high factor sun screen is essential.

• Role of androgens in acne
  Acne requires three components to come together: sebum production, retention, which favours the proliferation of Propionibacterium acnes, and the inflammation induced by the latter. Sebum production is regulated by androgens via receptors located in the sebaceous gland. In puberty, marked by the secretion of adrenal androgens (DHEA and DHEA sulphate), and then by that of more powerful androgens (Δ4-androstenedione, testosterone and dihydrotestosterone), the sebaceous gland starts to be stimulated. The single correlation highlighted in puberty between acne and androgens has been that with DHEA-S, which circulates in very high rates, without a common measure with that of other androgens.
  The sebaceous gland has all the enzymatic equipment necessary to transform androgens (DHEA-S into DHEA and then testosterone and finally dihydrotestosterone), so even a weak androgen such as DHEA-S can stimulate the gland. A gene anomaly, allowing the transformation of weak androgens into more powerful androgens, has not been highlighted. The sebaceous gland notably possesses a type 1 5α-reductase which converts testosterone into dihydrotestosterone (DHT), which has an even greater affinity for the androgens receptor (AR). There is an AR genetic polymorphism which modulates manifestations of androgenism, whether it is acne, hirsutism or androgenetic alopecia. The lack of effectiveness of the specific blocking of type 1 5α-reductase on acne tends to show that testosterone is also capable of acting directly on the gland without prior transformation.
  It seems that the exaggerated production of sebum by the sebaceous gland is not linked to the testosterone receptor itself but to a lack of repression of this receiver by the co-repressor located on the exon 1 linked to a decrease in the CAG triplets. The hyperactivity of 5α-reductase would not be primary but would be secondary to the androgenic effect itself, as 5α-reductase is an androgen-dependent enzyme.
• Other hormones involved in sebaceous production
  Oestrogens exert an inhibitory effect of sebum production via several mechanisms: They increase the carrier protein for testosterone (TEBG) and, thereby, reduce the rate of free hormones and block its expression; in a pharmacological dose, they have an inhibitory effect of 5α-reductase and sebum production.
  Many other hormones are involved in sebaceous production: growth factors (IGF), growth hormone GH, LXR receptor (which regulates the genes involved in the efflux of cholesterol and phospholipids), PPAR receptors (involved in growth, epidermal differentiation and lipid metabolism), among others.

A hormonal exploration is rarely necessary in women with acne

The objective of a hormonal exploration here would be to differentiate hyperandrogeny (increase in circulating androgens) and hyperandrogenism.
As there is no clear hyperandrogeny in the absence of a period problems, it is unnecessary to conduct a hormonal examination in a woman with acne with regular periods of 28 ± 2 days. An examination (estradiol, testosterone, FSH, LH, AMH and prolactin) is justified in the presence of irregular, persistent periods, 2 years after the onset of puberty.

The most frequent cause of period problems and hyperandrogeny is polycystic ovary syndrome (PCOS) affecting 30% of adolescent girls and 6% of adult women. The diagnosis in adults falls within the Rotterdam criteria (spaniomenorrhea, hyperandrogenism and presence of many follicles in the periphery of an increased volume ovary). These criteria cannot be used in teenagers. The increased rate of the Anti-Müllerian hormone (AMH) for some replaces the counting of microcysts by ultrasound. Unfortunately, the AMH rate is not currently standardised, nor is the number of microcysts by ultrasound, which depends on the ultrasound system used. There are other causes of hyperandrogeny, rare (ovarian or adrenal tumours, hypercorticism, etc.) and always associated with period problems. Only the congenital adrenal block which is revealed late, which can be accompanied by normal periods, in its heterozygote form, can be a problem.

Do not confuse hyperandrogenism and hyperandrogeny
Acne can be observed in the presence of hyperandrogeny, the most common cause in women is polycystic ovary syndrome (PCOS), or just a sign of hypersensitivity to androgens or hyperandrogenism.
Hyperandrogeny is not a necessary condition of hyperandrogenism, but the higher the circulating androgen levels, the more marked the hypersensitivity manifestations will be.>

In practice, a hormonal examination should be carried out after at least 2 months after stopping the pill (beware the risk of pregnancy!), on the 2nd or 3rd day of menstrual bleeding; In fact, an increase of Δ4-androstenedione, 17-OH progesterone or testosterone on the pill or in the 2nd part of the cycle cannot be interpreted.

What place is there for hormonal treatment for acne in women?

Hormonal treatment is usually suggested as the first-line treatment when there is a contraceptive desire. Taking into account the existing hyperandrogenic climate in women with acne, oestrogen-progesterone (a contraceptive pill) is traditionally suggested.

• The purpose of hormonal treatment for acne is to protect the sebaceous glands from the stimulation exerted by androgens, thus reducing the expression of the disease. This treatment only has an suspending effect, unlike retinoic acid which is probably the only treatment likely to have a definitive effect, without doubt by promoting apoptosis of sebaceous cells.
  Hormonal treatment, therefore, allows teenagers to wait for the desensitisation of the androgen receptor to intervene naturally. Be that as it may, if desensitisation has not occurred under treatment, acne will reappear following cessation and to the same extent as it would have done without treatment. This could also explain the onset of late or persistent acne, although there is little knowledge about receptor desensitisation mechanisms.
• The first hormonal treatment proposed to a young women who do not want to get pregnant is an oral oestrogen-progesterone contraceptive pill. Any pill decreases the rate of secretion of androgens, in particular in women with period problems and even more so in the case of PCOS. It is, therefore, active on hyperandrogenism and hyperandrogeny. All modern pills therefore work on acne. However, the main mechanism of the anti-androgenic effect passes through an increase in the carrier protein for testosterone SHBG. The SHBG rate depends on the oestro-androgenic hepatic relationship of the oestrogen-progesterone combination, therefore, a dose of ethinyl estradiol and the androgenic nature of the progestin. It is possible that some progestins (cyproterone acetate, drospirenone, chlormadinone acetate CMA) strengthen this effect by antiandrogenic properties.
• Pure progesterone contraceptive pills can promote or cause acne. This is generally not due to an androgenic effect of the progestin itself, but related to the decrease of TEBG by the the progestin by an antigonadotropic effect which lowers the rate of endogenous estradiol, hence an increase in the rate of free testosterone. An androgenic effect, even modest, can be attached to these mechanisms, specific to the progestin. Switching from an oestrogen-progesterone contraceptive to a progestin contraceptive is to avoid acne in the woman because it loses the benefit of the antiandrogenic effect linked to the increase in SHBG of this combination.
• And what do you suggest for women who do not want contraception?
  There is no hormonal acne treatment that is not contraceptive.
• Pills proven by clinical trials on acne
  Some first generation pills contained progestins with a powerful androgenic action, which cut the benefit of oestrogen, hence their responsibility for increasing acne outbreaks. These pills have now disappeared from the market, and more recent progestins are significantly less androgenic and much more antigonadotropic, and thus used in lower dose.
  The benefit of pills in studies versus placebo was assessed in the framework of a review Cochrane (Arowojolu AO and al. 2009 and 2012). Second generation pills with a low dose (100 μg) of levonorgestrel (LNG) and 20 μg ethinyl estradiol (EE) have demonstrated their efficacy on all parameters (total number of lesions, inflammatory and non-inflammatory lesions). 20 μg of EE is sufficient to obtain an antiandrogenic effect. Good results have also been obtained in studies with triphasic at norgestimate pills, as well as in studies assessing the combination drospirenone-EE and CMA-EE.
  In randomised studies (Arowojolu AO and Al.) that compared two pills with each other, a difference in efficacy on acne between the different third generation or between third and fourth generation pills was not highlighted; In fact, in a pill containing a nonandrogenic progestin, EE is the main anti-androgenic component. In contrast, a third generation pill would be slightly more effective for acne than a second generation 30 μg pill of EA due to the fact of the androgenic effect of LNG. Conversely, by decreasing the dose of LNG to 100 μg in a second generation pill associated with 20 μg of EA, you get anti-androgenic effect of the EE, which is manifested by better efficacy for acne versus the second generations 30 μg pills with 150 μg of LNG (Minidril®).
  Finally, the comparison of second and third generation 20 μg pills of EE shows a very slight superiority of the third generation (only one of the criteria studied was significantly different and only one of the evaluation times).

In practical terms

Hormonal treatment for a woman with acne must not just focus on acne, it must be designed taking into account all the expected risks and benefits of contraception.
Acne treatment depends on the type of acne present, its location and severity. It also depends on the context: age, desire to have a child, pregnancy, contraceptive history, etc.

The French health authorities recommend ordinary women take a second generation contraception with a 20 μg pill of EE combined with LNG,due to its best potential safety in terms of venous thromboembolic risk.

• In a woman with slight to moderate acne, and who does want not to get pregnant, this type of pill is suggested as the first-line treatment or the triphasic norgestimate pill.
• If the results on acne are insufficient, 6 months later you can try a third generation 20 μg EE pill.
• After failure, if you really want to improve the efficacy on acne, it will sometimes be necessary to prescribe a 30 μg EE pill combined with a third generation progestin (desogestrel, gestodene) and not second generation.
• The existence of a climate of hyperandrogeny can explain why acne does not improve or a relapse after apparently well managed anti-acne treatment. It is often a poorly adapted contraception - oestrogen-progesterone pills whose progestin is androgenic, pure progesterone pills, IUDs with progestins, implants -, that must also be changed.
• If after the failure of two courses of retinoic acid prescribed in the right dose and in consultation with the dermatologist, acne persists under oral oestrogen-progesterone contraception, it was previously legal to begin a treatment with a cyproterone acetate in a minimum dose of 25 mg, in combination with 25 μg of EE or with 2 mg estradiol due to its anti-androgenic effect.
• In women who do not want to take contraception (want to have a child, contraindication, etc.). There is no place for hormonal treatments.

When stopping taking the pill, acne may reappear; What is believed to be late acne that occurs when stopping taking the pill is, in fact, concealed acne. Similarly, acne will reappear when stopping cyproterone acetate.

• When acne is more severe, treatment with isotretinoin is possible. In women, the latter is not always prescribed because of legal constraints, including contraception, and difficulty monitoring it. However, any delayed treatment efficacy may have consequences, such as, in particular, permanent scars.
• In the face of these difficulties, we must adapt, and sometimes revisit our treatment strategy.

This article has been written by Dr. C. Jamin, gynecologist (Paris, France)