Unmasking hyperandrogenism: What clinical symptoms reveal about hormonal mysteries

INTRODUCTION

Hyperandrogenism, or androgen excess, is a medical condition characterized by excessive production and/or secretion of androgens by the ovaries and/or the adrenal glands where hirsutism, acne, and androgenetic alopecia (AGA) are some of the common clinical cutaneous manifestations. Hyperandrogenism is seen in around 7% of the reproductive age group females.^[1] Hirsutism, acne, and AGA may be seen in isolation or can present as part of an underlying hyperandrogenic state in 30–50% of patients.^[2] It was Bullock and Sequeira who in 1905 first brought up the association between masculinisation and endocrine pathology.^[3]

These manifestations are fairly common, where hirsutism is seen in around 60–83%, acne in 11–43%, and AGA in 25% of females.^[1,4,5] Other clinical manifestations of hyperandrogenism include weight gain, acanthosis nigricans, striae, menstrual irregularity, infertility, virilization, and pelvic mass. There is an increase in hirsutism with age due to more duration of exposure to androgens.^[6]

Cutaneous hyperandrogenism can signify an idiopathic skin disease or a systemic disorder like polycystic ovary syndrome (PCOS), the most commonly diagnosed underlying condition in about 80–85% of reproductive age women.^[7] Other causes include non-classic congenital adrenal hyperplasia, androgen-secreting tumors, Cushing syndrome, thyroid dysfunction, hyperprolactinemia, and the use of specific drugs (e.g., testosterone, dehydroepiandrosterone sulfate, danazol, corticotropin, high-dose corticosteroids, metyrapone, phenothiazine derivatives, anabolic steroids, androgenic progestin, and acetazolamide).^[7-9] Idiopathic hirsutism (5–20% of cases) is characterized by regular menses without androgen excess.^[10,11] It can be due to disorders in peripheral androgen activity and is often associated with a positive family history.^[12]

Among the various disorders presenting with cutaneous hyperandrogenism, history including age, onset of symptoms, chronology, and progression helps to identify likely diagnoses. For example, females <35 years of age with slow hair growth and the presence of menstrual irregularities shortly after puberty have a high possibility of PCOS^[13] whereas ones more than 35 years, with rapid excessive hair growth, deepening of the voice, and breast atrophy would more likely be a case of adrenal or ovarian tumor.

The purpose of this article was to review the occurrence of cutaneous manifestations, laboratory abnormalities, underlying etiopathology, and their relative frequency, along with finding an association among severity of clinical features and levels of androgenic hormones if any in patients with hyperandrogenism.

MATERIALS AND METHODS

In this cross-sectional study, 200 female patients aged 15–60 years with clinical signs of hyperandrogenism from the dermatology department of a tertiary care hospital in India from August 2016 to October 2018 were included in the study.

RESULTS

Etiology

In this study, PCOS [Figure 1] was the leading diagnosis, affecting 120/200 (60%) patients, followed by idiopathic hirsutism (39/200; 19.5%), familial (16/200; 8%), and adrenal (13/200; 6.5%). Hypothyroidism and hyperprolactinemia were less common (4/200; 2% each); 2/200 (1%) each had ovarian androgen-secreting neoplasm [Figure 2] and Cushing syndrome [Figure 3] affecting 4/200 (2%) patients [Table 6].

Table 6: Comparison of etiology of hyperandrogenism by various studies

Etiology	Malik et al., 2007[16]	Ansarin et al., 2007[11]	Ahmad et al., 2009[15]	Chhabra et al., 2012[21]	D Sharma et al., 2012[17]	Pathania et al., 2020[20]	Dhanotia et al., 2020[19]	Mahajan et al., 2020[18]	Present Study
PCOS	44.6%	62.53%	11.43%	70%	38%	72%	38.64%	29.5%	60%
Idiopathic hirsutism	47.3%	35.19%	80%	15%	50%	13%	43.18%	10.7%	19.5%
Familial	-	-	-	-	-	-	-	1.6%	8%
Adrenal hyperandrogenism	1.3%	0.38%	2.86%	7.5%	4%	-	-	-	6.5%
Hypothyroidism	4%	-	5.70%	7.5%	8%	3%	-	-	2%
Hyperprolactinemia	-	0.13%	-	-	-	1%	-	10.7%	2%
Ovarian androgen-secreting neoplasm	-	-	-	-	-	-	-	-	1%
Cushing disease/syndrome	2.7%	-	-	-	-	-	-	-	1%
Iatrogenic	-	-	-	-	-	4%	-	-	-

PCOS: Polycystic ovary syndrome

Close

Figure 1:

Cutaneous findings found in PCOS females. (a) Hirsutism. (b) Acne vulgaris (grade III). (c) Acanthosis nigricans. PCOS: Polycystic ovary syndrome.

Export to PPT

Close

Figure 2:

Cutaneous features seen in patients with ovarian androgen-secreting tumors. (a) Severe hirsutism with m-FG of 31. (b) Male-pattern androgenetic alopecia (grade-III) in the patient.

Export to PPT

Close

Figure 3:

Cutaneous findings in the patient with Cushing syndrome due to pituitary adenoma. (a) Cushingoid facies of the patient. (b) Hirsutism. (c) Purple striae over the shoulder, upper chest, and abdomen. (d) Buffalo hump.

Export to PPT

DISCUSSION

This study provides a comprehensive overview of cutaneous manifestations associated with hyperandrogenism, exploring their occurrence, laboratory abnormalities, and underlying etiologies.

The majority of our patients were aged 20–29 years, aligning with previous research indicating that this is a common age for hirsutism onset.^{[7-9,12,15-22]} The higher frequency of unmarried women in our cohort may reflect cultural or societal influences as seen in other studies.^[17,18,21] Patients typically sought help after an average of 4.14 years, consistent with reported durations in similar studies.^[19,21] A family history of hyperandrogenism was present in 15.5% of cases, echoing previous findings^[9,21] but with some variation.^[15,18]

Hirsutism was observed in 99% of patients, with a mean mFG score of 17.05 ± 6.37, comparable to some studies^[16,18] but higher than others.^[7,9,20] Notably, severe hirsutism was observed in 8.5% of the cases, aligning with findings that link severe symptoms to higher androgen levels. Alopecia was noted in 61.5% of patients, with AGA affecting 13.5%. Acne and oligomenorrhea were prevalent in 54.5% and 35% of patients, respectively. A significant association between menstrual irregularities and PCOS was found, aligning with other studies.^[17,21] This is in line with the association between menstrual irregularities and hyperandrogenic states. Infertility, reported in 20.9% of married women, underscores the reproductive impact of hyperandrogenism, with PCOS being the predominant cause.

Hormonal profiles revealed elevated LH/FSH ratios in 62.5% of patients, with most having PCOS which aligns with several studies.^{[16,18,21,23]} Elevated serum total testosterone was seen in 71% of patients, consistent with several studies,^[16,20] though variation exists.^[15,19] Serum-free testosterone was elevated in 47% of patients, with a significant association with PCOS. Elevated total testosterone and free testosterone levels were notably higher in patients with PCOS, while ovarian tumors exhibited the highest levels of these hormones. This highlights the importance of differentiating between PCOS and other conditions such as adrenal or ovarian tumors based on hormonal profiles. No significant correlation was found between the severity of hirsutism and free testosterone levels in our study, aligning with others,^[24] but some found a significant association between them.^[18,21,25] Similarly, no significant association was found between the severity of hirsutism and total testosterone and DHEAS levels in the present study, similar to others^{[18,21,24,25]} while Pathania et al.,^[20] found a significant association between raised serum total testosterone and severity of hirsutism. In addition, other clinical features such as hyperandrogenism and obesity showed no significant correlation with hormonal levels, consistent with Pathania et al.^[20]

Interestingly, elevated serum DHEAS was noted in 23.5% of patients, with the highest levels observed in ovarian tumor cases. In ovarian tumors, particularly androgen-secreting tumors like Sertoli-Leydig cell tumors, the elevation of DHEAS may occur alongside other androgens such as testosterone. While DHEAS elevation is more commonly associated with adrenal causes, the presence of high levels in ovarian tumors can provide diagnostic insight, especially when considered alongside clinical features such as virilization, hirsutism, or menstrual irregularities. Thus, DHEAS measurement, while not diagnostic on its own, can aid in distinguishing between adrenal and ovarian sources of hyperandrogenism when combined with imaging and other hormone evaluations.

Biochemical hyperandrogenemia was found in 67.5% of patients, with a higher frequency in those with PCOS (8.75%) compared to non-PCOS patients. These findings are consistent with Chhabra et al.,^[21] who reported 71.43% of PCOS patients with hyperandrogenemia, and Steinberger et al., who also observed significantly elevated androgen levels in PCOS patients.^[26]

PCOS was the most common cause of hirsutism, present in 60% of patients, with idiopathic hirsutism and familial cases being the next most frequent. Adrenal causes were identified in 6.5% of patients, including both benign and malignant conditions. We observed elevated androgen and 17-OHP levels in patients with late-onset congenital adrenal hyperplasia. Clitoromegaly was noted in three patients with adrenal hyperandrogenism, and one patient with clitoromegaly had an ovarian androgen-secreting tumor. According to literature, these androgen-secreting tumors are relatively rare affecting one per 300–1,000 hirsute patients. Virilizing ovarian tumors constitute <0.2% of cases of hyperandrogenism.^[27] This higher incidence of ovarian tumors in our study may be influenced by the referral of patients from our cancer institute, potentially skewing incidence figures.

Hypothyroidism and hyperprolactinemia were less common, and Cushing syndrome was present in 1% of cases. Table 6 illustrates the comparative underlying etiology of hyperandrogenism in several studies.

Overall, our study underscores the importance of a comprehensive evaluation in patients with hyperandrogenism, considering a range of potential causes and associated hormonal abnormalities.

CONCLUSION

This study underscores the importance of integrating hormonal evaluations with clinical observations to differentiate between physiological and pathological hyperandrogenism. Dermatologists often encounter the cutaneous manifestations of hyperandrogenism, positioning them as key players in its early detection and management. Despite the clinical and biochemical markers of hyperandrogenism often presenting in isolation, a thorough hormonal workup remains crucial for accurate diagnosis and tailored treatment. Moreover, it must be bear in mind that hyperandrogenemia is more detrimental to women’s health than clinical hyperandrogenism making it necessary to perform hormonal investigations for susceptible patients. Given that facial hair remains a primary concern for patients seeking dermatological care, our findings highlight the need for dermatologists to adopt a proactive approach to investigating underlying causes and managing associated metabolic abnormalities. While this study provides valuable insights, further research with larger samples and more refined methodologies is essential to enhance our understanding and management of hyperandrogenism.