Overview 

Nodular acne is a common but severe type of inflammatory acne. Although not deadly, nodular acne can cause discomfort and lower self-esteem. Like many types of acne, it causes red bumps deep under the skin. However, It differs from other types of acne as nodular acne does not have a whitehead or a blackhead in the centre.¹ Hormones are known to be one of the main sources of nodular acne. This article will discuss what nodular acne is, the different roles of hormones in acne development, and different treatments for nodular acne.

Treatments of nodular acne^1,2

Isotretinoin is used to treat severe nodular acne and is viewed as a standard.³ However, alternative therapies listed can also target the pathogenesis of nodular acne.

Treatments include:

• Antibiotics like tetracycline (kill the bacteria trapped in the pores)
• Contraceptives
• Prescription topical medicine like benzoyl peroxide, salicylic acid, retinoids
• A combination of antibiotics and prescription topical medicine may be used 
• Cortisone injections 

Potential side effects of nodular acne^2,4

• Dry skin 
• Severe scarring 
• Sun-sensitive skin
• Headaches
• Pain and aches 
• Nodules may feel like knots under the sun

Risk factors

• Genetics 
• Medications like corticosteroids, anabolic steroids, tumour necrosis factor (TNF) inhibitor etanercept, imatinib⁵
• Conditions like hyperhidrosis which causes excessive sweating
• Undergoing a haemodialysis procedure
• Certain supplements 
• Overactive oil glands 
• Diet⁶
• Hormonal changes (increase in androgen hormones)
• Intake of endocrine-disrupting chemicals⁷
• Build-up of dead skin cells in pores 

Nodular acne and hormones 

Hormones are known to have a significant influence on the development of nodular acne. Young people going through puberty and thus undergoing hormonal change are therefore a huge group that is susceptible to nodular acne. It is known that an increase in androgen causes excess sebum production, thus causing the clogging of pores.⁸ It is known that biological men, pregnant, menstruating or menopausal biological women also have a higher risk of getting nodular acne. Additionally, patients with androgen excess syndrome are also likely to develop nodular acne. 

Nodulocystic acne

Nodulocystic acne is a more severe form of nodular acne.⁹ It is a combination of cystic acne and nodular acne. Cystic acne causes deep, painful, fluid-filled acne, meanwhile, nodular acne causes more hard and firm lumps. Similar to nodular acne, it causes inflammation, breakouts, pain and scarring. In terms of hormonal causes of nodulocystic acne, it is similar to nodular acne and is caused by an excess of androgen.¹⁰ It is known that nodular acne, cystic acne and nodulocystic acne are used interchangeably at times, even in an academic context.¹¹ 

Roles of hormones in acne development

Androgen is known to be essential in the development of acne. With supporting clinical evidence showing a higher observation of acne during puberty, menstruation and hyperandrogenic states, androgen is widely known as a key factor.¹² Androgen is involved in the synthesis of sebum in sebocytes. This increases the chance of inflammation and acne formation. Regulating androgen receptors is therefore important in severe acne cases.¹³ 

The development of acne is known to involve different hormonal pathways. 

These pathways include hormones like IGF-1 (insulin-like growth factor), androgen, corticosteroids and estrogen. When these pathways are interfered with, for example, when the endogenous hormone level increases or when androgen receptor ligand functions are altered, acne is more likely to develop.⁷ It is known that the level of IGF-1 increases during puberty, causing a higher occurrence of nodular acne in teenagers undergoing puberty.¹⁴

Additionally, clinical evidence also states that testosterone, androstenedione, and cortisol concentrations correlate with acne severity.¹⁵ 

Sex hormones and acne

A cross-sectional study that compared the correlation between sex hormones and the development of acne provided an overview of the relationship between sex hormones and the severity of acne. The study found that the ratio of androgen to estrogen levels is positively correlated while the level of estradiol is negatively correlated with the severity of acne in both sexes. Meanwhile, the level of FSH (follicle-stimulating hormones) in people assigned female at birth (AFAB) are also positively correlated to the severity of acne. As the severity of acne increases as the ratio of androgen to estrogen increases, and the level of the two hormones can be used as an indicator of acne.¹⁶ In people assigned male at birth (AMAB), a higher level of testosterone is also known to trigger the development of acne. An increase in the production of sebum is generally observed in individuals with higher testosterone levels. Additionally, testosterone may also lead to overgrowth of skin cells, leading to acne growth.¹⁷

People assigned male at birth and nodular acne 

Androgen hormones like testosterone and dihydrotestosterone are known to adjust the skin microbiome and trigger inflammation.¹⁸ These hormones primarily increase the production of skin oil (sebum). More skin oil usually causes more acne as an excessive amount of sebum increases inflammation. Additionally, testosterone may also lead to an overgrowth of skin cells, which may lead to clogged pores. The mix of excess sebum with clogged pores allows follicles to be clogged and a perfect environment for bacteria to grow and form acne.¹⁹ 

People assigned female at birth and nodular acne 

People assigned female at birth (AFAB) during the menstrual cycle may experience a higher likelihood of acne development. This is due to a sudden rise of androstenedione and testosterone during the mid and luteal phases of the menstrual cycle.²⁰ Another study that measured the relationship between acne and hormones in people AFAB during puberty found that adrenal androgen (DHEAS) is related to the maturation of sebum production, therefore leading to an increased likelihood of acne occurrence.²¹ 

Nodular acne is also more common in pregnant people and menopausal people AFAB. In women who are undergoing menopause, there is a decreased level of estrogen and progesterone. This can lead to an increase in androgen, thus causing menopausal acne to occur.²² In pregnant people, hormonal fluctuations are usually observed. Particularly, as estrogen and progesterone fluctuate and decrease, the likelihood of nodular acne occurring in pregnant people increases.²³ 

Hormonal treatments for nodular acne 

Hormonal therapy for nodular acne can be used in combination or as monotherapy. As androgen is the primary hormonal factor that is causing nodular acne, androgen antagonists or anti-androgenic agents are mainly used.²⁴ In Europe, cyproterone acetate (Androgen antagonist) and ethinylestradiol are usually used to treat acne. Meanwhile, in America, spironolactone and oral contraceptives are used to treat people AFAB with premenstrual acne flares, jaw-line acne and severe nodular acne caused by polycystic ovarian syndrome (PCOS).

Androgen antagonists and anti-androgenic agents work by decreasing androgen levels, thus regulating the secretion of sebum. Androgen antagonists increase sex hormone-binding globulin produced by the liver. This decreases luteinising hormones and avaliable free testosterone. Additionally, the treatments also suppress testosterone. An example of an anti-androgenic drug is spironolactone. It works by inhibiting aldosterone and 5α-reductase competitively. It is commonly used to treat people AFAB with nodular acne caused by polycystic ovarian syndrome.

Oral contraceptives also have anti-androgenic effects. Norgestimate, ethinylestradiol and levonorgestrel are used in combination or individually depending on the severity.³ Estrogen and progestin are also used to treat hormone-related acne. These oral contraceptives allow the reduction of nodular acne by reducing levels, thus inhibiting sebaceous gland activity.

Possible long-term side effects of the hormonal treatments:²⁵

• Loss of libido
• Diarrhea
• Erectile dysfunction
• Painful, lumpy or tender breasts
• Fatigue
• Depression
• Mood changes
• Dizziness
• Bleeding Gums
• Building up of fluids
• Drastic change in weight 
• Shortness of breath

Summary

Nodular acne is a severe form of inflammatory acne. Hormonal influence, particularly androgens are the primary cause of the development of nodular acne. It is therefore important to understand the impact of different hormones on nodular acne to effectively treat and manage the acne. It is known that hormonal fluctuations in different stages of life like puberty, pregnancy and menopause could increase the risk of nodular acne development. It is important to seek medical help if one is suffering from severe acne. Currently, a combination of treatments like isotretinoin and hormonal treatments like oral contraceptives and anti-androgens are being used to treat nodular acne. However, further research and trials are required to further refine these treatments.