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Abstract

Polycystic ovary syndrome (PCOS) is an essential differential diagnosis of hyperandrogenism to consider in women, with most women presenting with irregular menses, infertility, and hirsutism. The diagnosis is challenging because it is a heterogenous disorder with significant variations in its associated features. Classic PCOS (hyperandrogenism plus ovulatory dysfunction) affects about 10% of reproductive-age women. Hyperandrogenism (clinical, biochemical, or both) is a hallmark of the syndrome. Approximately 60–76% of PCOS women are hirsute and hyperandrogenemia is observed in 75–90% of these women. Androgen assays are not always reliable at the lower levels detected in women with PCOS. This article will attempt to review the pathophysiology and controversies of hyperandrogenism in PCOS women, its clinical and biochemical presentations, and management.

Introduction

The diagnosis of polycystic ovary syndrome (PCOS) requires two of the following abnormalities: clinical or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology as well as the exclusion of mimicking conditions such as Cushing syndrome (1 mg dexamethasone suppression test) especially when hypogonadotropic hypogonadism is present, nonclassical congenital adrenal hyperplasia (early follicular-phase early-morning plasma level of 17-hydroxy progesterone), hyperprolactinemia (prolactin level), and thyroid dysfunction (thyroid stimulating hormone and free thyroxine). First described by Stein and Leventhal in 1935, this condition has been called “polycystic ovary disease,” with many today proposing that “polycystic ovary syndrome” is best used.

This article will attempt to review the pathophysiology and controversies of hyperandrogenism in PCOS women, its clinical and biochemical presentation, and management.

Normal Physiology of Androgens in Women

Androgens have a role in female health and contribute to bone density, muscle mass, and female sexual function. Androgens include dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone. Testosterone and dihydrotestosterone are the most biologically active.¹ Androgen biosynthesis occurs in the ovaries (25%), adrenal gland (25%), and peripheral tissues (50%) such as the liver, skin, and fat.² Table 1 summarized the source and estimated normal concentrations of androgen in women, which may vary with the laboratory.

Table 1.

Androgens in Women

Androgens	Reference range		Source			Comments
Androgens	Reference range		Ovary (25%)	Adrenal (25%)	Periphery (50%)	Comments
DHEA-S	18–29 years	44–332 μg/dL (1.19–9.00 μmol/L)	None	100%	None	Modulated by ACTH. Influenced by prolactin, IGF-1, and estrogen levels
	30–39 years	31–228 μg/dL (0.84–6.78 μmol/L)
	40–49 years	18–244 μg/dL (0.49–6.61 μmol/L)
DHEA	100–1000 ng/dL (3–35 nmol/L)		20%	50%	30% (from DHEA-S)
Androstenedione	30–200 ng/dL (1.05–6.98 nmol/L)		50%	50%	None	Circadian and menstrual cycle variation. Suppressed by corticosteroid
Testosterone	Total: 8–60 ng/dL (0.3–2.1 nmol/L) Free: 0.3–1.9 ng/dL (0.01-0.07 nmol/L)		50%	25%	25% (from androstenedione)	Circadian and menstrual cycle variation. Most biologically active
Dihydrotestosterone	2 ng/dL		None	None	100% (from testosterone)	Most biologically active

Table adapted from Burger.¹

ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; IGF-1, insulin-like growth factor 1.

Numerous studies suggest that androgen insufficiency diminishes women's sexual desire and energy,³ although it is not conclusive that treatment with testosterone increases libido.⁴ The differential diagnosis of hyperandrogenism is generally divided by adrenal (Cushing syndrome and congenital adrenal hyperplasia) versus ovarian (PCOS, hyperthecosis, and carcinoma). Whereas mild hyperandrogenism is characterized by hirsutism, acne, and male-pattern baldness, severe androgen excess results in virilization (voice deepening and clitoromegaly), suggesting the possibility of ovarian hyperthecosis or androgen-secreting tumor. Most guidelines recommend further evaluation if the DHEA-S concentration is >700 μg/dL (>19.0 μmol/L)⁵ or serum total testosterone concentration exceeds 150 ng/dL (>5.2 nmol/L).⁶

Ovarian hyperthecosis has sometimes been referred to as an extreme form of PCOS. It is a non-neoplastic condition of androgen excess classically described by the presentation of significant and progressive hirsutism or virilization due to ovarian interstitial cells differentiation into active luteinized theca cells capable of producing androstenedione and testosterone. Total testosterone concentration is usually >150 ng/dL and almost all women have obesity and hyperinsulinemia. It is more common in postmenopausal women. The diagnosis is confirmed histologically.⁷

Diagnosis of PCOS

There is no specific test to diagnose PCOS, rather three sets of criteria have been developed for PCOS diagnosis. Each set involves different combinations of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology⁸ (Table 2). As defined by the National Institutes of Health diagnostic criteria (hyperandrogenism plus ovulatory dysfunction), “classic” PCOS affects 6–10% of reproductive-age women. The prevalence rate is almost twice as high under the broader Androgen Excess and PCOS society criteria (hyperandrogenism plus ovulatory dysfunction or polycystic ovarian morphology).⁹

Table 2.

Diagnostic Criteria for Polycystic Ovary Syndrome

Variable	National Institutes of Health	Rotterdam	Androgen excess and PCOS society
Hyperandrogenism^a	+	≥2 of 3 criteria	+
Ovulatory dysfunction^b	+		≥1 of 2 criteria
Polycystic ovarian morphological features^c	−		≥1 of 2 criteria

Table derived from McCartney et al.⁸

Clinical (hirsutism assessed by the Ferriman–Gallwey scale, acne, and male-pattern hair loss) or biochemical hyperandrogenism (total and/or free testosterone, androstenedione, and/or DHEA-S level above the upper 95th percentile of 98 healthy non-hirsute eumenorrheic women).

Menses are interval <21 days or >35 days or eumenorrhea with progesterone <3 to 4 ng/mL a week before anticipated menses (days 21 or 22).

Polycystic ovarian morphological features are defined as 12 or more antral follicles (2–9 mm in diameter) in either ovary, an ovarian volume that is >10 mL in one or both ovary.

PCOS, polycystic ovary syndrome.

Because of the overlap between normal pubertal physiology changes and PCOS clinical features, the diagnosis should not be made within 2 years of menarche.¹⁰ In practice, the diagnosis of PCOS is usually a challenge because it is a heterogenous disorder with significant variations in its associated features.

Clinical and Biochemical Hyperandrogenism

Hyperandrogenemia is the biochemical hallmark of PCOS. High levels of androgens are detected in 75–90% of PCOS patients with oligomenorrhea,^11,12 and their concentrations often increase with the severity of the phenotype.¹³ Hyperandrogenemia is defined as a free/total testosterone, androstenedione, and/or DHEA-S level above the upper 95th percentile of 98 healthy non-hirsute eumenorrheic women.¹⁴ Testosterone assays (free/total testosterone) have low specificity and sensitivity at the lower levels detected in PCOS women. When measured, total testosterone level is preferably drawn early morning, during the early follicular phase of the menstrual cycle.

Mass spectrometry–based assays of total testosterone may be more precise compared with other clinical assays.¹⁵ Calculated free testosterone or free androgen index (FAI) [(total testosterone × 100)/sex hormone–binding globulin (SHBG)] further increases the diagnostic accuracy. FAI ≥6 is considered abnormal. Androstenedione appears to be a more sensitive test to assess for androgen excess compared with testosterone levels.¹⁶ In a study of 86 PCOS women fulfilling the Rotterdam criteria, elevated serum testosterone level was found in 65%, whereas serum androstenedione concentrations were above the reference range in 88%.¹⁷ Although the ovaries are the main source of hyperandrogenemia in PCOS,¹⁷ elevated levels of adrenal DHEA-S are seen in 25–35% of these women.^11,12

Clinical manifestations of hyperandrogenemia are hirsutism, acne, and androgenic alopecia. Hirsutism is a more specific feature of hyperandrogenism than acne and alopecia. Hirsutism is defined as excessive terminal hair that appears in a male pattern in women. The Ferriman–Gallwey (FG) scale quantitates the extent of hair growth in different androgen-sensitive sites. A score of 8 or more on the FG scale indicates that a woman is hirsute.¹⁸ Ethnic variations add to the challenge in the interpretation of the FG score. A score of 8–15 indicates mild hirsutism, and a score >15 indicates moderate or severe hirsutism. Among PCOS patients, ∼60–76% are hirsute,¹⁹ with an average score of 8 ± 5.²⁰ Hirsutism results from the interaction between androgen levels and the sensitivity of the hair follicle to androgen.¹⁸

A free testosterone level that is at least twice the upper limit of normal will result in some degree of hirsutism.²¹ However, the severity of hirsutism does not correlate well with the androgen levels.¹⁸ Insulin has direct effect on hair follicle growth and the severity of hirsutism may be a result of differences in the degree of hyperinsulinism. Lower levels of hyperinsulinism are associated with lower androgen levels and less severe hirsutism, whereas higher levels of hyperinsulinism favor the development of hirsutism and worsening hyperandrogenemia.²²

Androgens also stimulate sebocytes and follicular keratinocytes leading to their hyperplasia and the impaction of the pilosebaceous unit that characterize acne.¹⁸ Androgenic alopecia is a male-pattern hair loss involving the anterior, mid, or temporal scalp and/or the vertex of the scalp and is the result of circulating androgens that suppress hair growth on the scalp.¹⁹

Pathophysiology: Hyperandrogenemia and Hyperinsulinism

The identification of the primary underlying pathophysiology of PCOS is still unclear. Clinicians and investigators have debated whether the primary event is ovarian, pituitary, or hypothalamic in origin, or related to obesity and its hyperinsulinism (Fig. 1).

FIG. 1.

PCOS pathophysiology. DHEA-S, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; SHBG, sex hormone–binding globulin.

PCOS is characterized by an increased frequency of gonadotropin-releasing hormone (GnRH) pulsatility that selectively increases luteinizing hormone (LH) secretion.²³ LH stimulates multiple steroidogenic enzymes in the theca cells of the ovary, leading to theca cell hyperplasia and increased testosterone production.²⁴ Because of relative follicle-stimulating hormone (FSH) deficiency, testosterone is not completely aromatized and degraded by the granulosa cells.

The increased levels of testosterone feeds back on the hypothalamus, decreasing the ability of estradiol and progesterone to slow down GnRH pulse frequency.²⁵ The ovaries do not appear to be the primary abnormality in PCOS since they have the ability of responding promptly to changes in gonadotropin secretion; ovulation occurs in response to the surge in secretion of FSH stimulated by clomiphene citrate. Furthermore, weight reduction in obese patients reduces estrone and insulin levels, normalizes gonadotropin secretion, and regulates menstrual cycles in women with PCOS.^26,27

The PCOS pathophysiology may originate centrally at the pituitary level and is explained by the preferentially inhibitory action of estrogen on FSH release coupled with a relative insensitivity of FSH release. This is supported by the observation that among postmenopausal women, PCOS women had lower FSH levels and SHBG and higher FAI compared with controls matched for weight, BMI and waist-to-hip ratio. The two groups did not differ in regard to LH level, DHEA-S, androstenedione, total testosterone, estradiol, and estrone.^28,29 Furthermore, in the largest most comprehensive association study of PCOS genotype, mutations in the region of the FSH-beta gene were identified that positively correlate with an elevation in circulating LH concentration.³⁰ LH release does not appear to be the major defect in PCOS as there is evidence of an intact positive feedback mechanism of estrogen on LH release and surge.³¹

Hyperinsulinemia also plays a major role in patients with PCOS and it is exacerbated by hyperandrogenism-related visceral fat accumulation.²⁵ Hyperinsulinemia stimulates the hypothalamic–pituitary–adrenal axis both centrally³² and peripherally,^32,33 leading to increased adrenal androgen production. DHEA-S levels are associated with insulin resistance in women with PCOS.³⁴ Insulin and testosterone decrease hepatic production of SHBG, elevating the levels of free testosterone.³⁵ Testosterone, in return, decreases the sensitivity of the feedback effects of estradiol and progesterone on the hypothalamus and pituitary.¹⁹

Insulin resistance is the reduced ability of insulin to mediate its actions on glucose metabolism resulting in an increased amount of insulin. Insulin sensitivity is measured with the following techniques, arranged according to their accuracy: fasting glucose, homeostasis model assessment (HOMA), oral glucose tolerance test (OGTT), frequently sampled intravenous glucose tolerance test (FSIVGTT), and euglycemic hyperinsulinemic clamp.²⁵ The prevalence of insulin resistance in PCOS women was 53% for the modified FSIVGTT,³⁶ 23–35% for impaired glucose tolerance, and 4–10% for type 2 diabetes mellitus.²⁵ The increase in insulin responses during OGTT was two times higher than age- and weight-comparable reproductively normal control women.²⁵

Management of Hyperandrogenism

Hirsutism can be managed with direct hair removal methods and with medical therapies against androgen production and action. Mechanical hair removal (shaving, plucking, and waxing) is recommended for mild hirsutism and if not effective, pharmacological therapy (combined oral contraceptive pills and antiandrogens) is added.⁵

Combined oral contraceptives pills are the hallmark treatment of PCOS to reduce hyperandrogenism through different mechanisms. They suppress LH and, therefore, ovarian androgen secretion, and stimulate the production of SHBG from the liver, which increases androgen binding and reduces serum-free androgen concentrations.³⁷ Progestins also increase testosterone clearance.³⁸ All combined oral contraceptive pills appear to be equally effective for hirsutism,⁵ reducing FG scores by 7 points⁵ with the hirsutism scores almost reaching that of control group of non-hirsute women.³⁹ The changes in the hair thickness become visible after at least 6 months of therapy. Antiandrogen therapy can be added if suboptimal response after 6 months⁸ (Table 3). There is also evidence that oral contraceptives decrease the severity of acne in women with PCOS.⁴¹

Table 3.

Hirsutism in Women with Polycystic Ovary Syndrome (Average Ferriman–Gallwey Scores of 8 ± 5)

Severity of hirsutism	Management of hirsutism	Response to management
Normal: FGS <8 Mild: 8–15 Moderate—severe: >15	Mechanical hair removal	Effective for mild hirsutism
	OCP	↓ FGS by 7
	Antiandrogens (combined with OCP) • Spironolactone (up to 100 mg/d) • Finasteride (up to 5 mg/d)	↓ FGS by 4
	Weight loss	Observed with 35% weight loss

Table derived from Swiglo et al.⁴⁰

FGS, Ferriman–Gallwey scores; OCP, combined oral contraceptive.

Antiandrogen therapy includes spironolactone (aldosterone-antagonist), finasteride (5α-reductase inhibitor), and flutamide (androgen receptor antagonist). Daily spironolactone 100 mg, finasteride 2.5–5 mg, and flutamide 500 mg improve hirsutism scores compared with placebo, reducing FG scores by 2–5 points and by 4 points on average and by 15–40% within 6 months after the start of therapy.⁴⁰ There was no significant difference in effectiveness among the three antiandrogens, although spironolactone is often prescribed because of its relative favorable safety profile.

Flutamide is no longer a recommend option because of hepatotoxicity risk.⁵ The maximal effectiveness of spironolactone occurs at about 3 months and continues at 12 months after initiating treatment.⁴² Spironolactone may mildly reduce circulating androgen levels, which may further contribute to the progressive regression of hirsutism.⁴² There is a danger that a male fetus could be feminized in women taking antiandrogens and, therefore, a reliable contraception must be used.

As discussed earlier, lower insulin levels are related to lower androgen levels and less severe hirsutism in women with PCOS.²² Insulin-lowering drugs and insulin sensitizers such as metformin and thiazolidinediones are not more effective than placebo for hirsutism treatment,⁵ despite lowering serum testosterone levels by ∼20–25% in women with the PCOS.⁸ However, subgroup analyses showed that insulin sensitizers may be more effective than placebo in overweight and obese women treated for >6 months.⁴³

Weight loss also lowers insulin levels. Loss of at least 5% of body weight in overweight and obese patients with PCOS lowers androgen levels (total and free testosterone, FAI, and DHEA-S), increases SHBG, improves insulin sensitivity (OGTT, HOMA, fasting glucose, and insulin levels), and decreases hirsutism.⁴⁴ These findings are particularly pronounced after excessive weight loss, such as in the context of bariatric surgery.^45,46 In one study, hirsutism had resolved in 29% of women with obesity after 35% weight loss by gastric bypass with a mean follow-up of ∼4 years.⁴⁷ There are no randomized trials and no long-term data on hyperandrogenism and metabolic outcomes with weight loss.

Fertility and PCOS

PCOS is one of the leading causes of infertility among women of reproductive age. Ovulatory dysfunction is characterized by chronic anovulation in the presence of normal FSH and estradiol concentrations. This is in contrast to conditions such as hypercortisolism and hyperprolactinemia that suppress the hypothalamic-pituitary-ovarian signaling and lead to secondary amenorrhea characterized by estrogen deficiency. As previously discussed, the relative FSH deficiency increases testosterone production. In turn, testosterone decreases the normal feedback effects of estradiol and progesterone on GnRH pulse frequency, preventing LH surge and ovulation. Hyperinsulinemia increases adrenal androgen production, further exacerbating the situation.

Considering the prevalence of obesity and hyperinsulinism, it seems reasonable to assume that weight reduction in women with PCOS would provide benefit. Indeed, modest weight loss of 5–10% has been associated with resumption of ovulation.⁴⁸ Higher the weight loss has been associated with better menstrual cycle regulation and fertility. Lifestyle interventions results in a mean weight loss of 5–8%. Glucagon-like peptide-1 receptor agonist is now emerging as a therapeutic option for obese women with PCOS. Liraglutide is the most studied option in this group and is associated with 5–6% weight loss. Most studies report improved menstrual patterns with Liraglutide. There is also evidence of increased spontaneous pregnancies and improved in vitro fertilization pregnancy rates.⁴⁹

Semaglutide has not been studied in PCOS, but it is an attractive option as it has more impact on weight loss (up to 15%).⁵⁰ Bariatric surgery is an alternative strategy for weight loss in women with PCOS. Based upon several small observational studies, all obese women who lost weight after Roux-en-Y gastric bypass had restored menstrual cycles at approximately 3–4 months after the operation and an increased ability to conceive within 2 years of surgery.^45,51,52 Ovulation induction is expensive and not very effective. The live birth rate among women who received clomiphene and aromatase inhibitor letrozole was about 20–30%.⁸ Current guidelines recommend against the routine use of metformin in obese women with PCOS for infertility, because although it increases ovulatory rates and pregnancy rates, it does not improve live birth rates.⁵³

Controversies

PCOS women are at increased risk for metabolic syndrome, as evidenced by a higher prevalence of insulin resistance, type 2 diabetes mellitus, dyslipidemia, and hypertension. This risk is above what is observed in simple obesity.⁵⁴ The hyperandrogenic phenotype, in particular, appears to have the highest risk of metabolic syndrome. One putative mechanism is that androgens excess increases adipose tissue lipid accumulation, leading to insulin resistance. Hyperinsulinemia then further exacerbates androgen generation.⁵⁵ Interestingly, women with isolated hyperandrogenemia have normal insulin sensitivity in comparison with PCOS patients.^56,57 Furthermore, gender-affirming testosterone therapy does not decrease insulin sensitivity and may even be associated with an improvement.⁵⁸

Screening for cardiometabolic risk factors is recommended and includes measurement of the weight, body mass index (BMI), waist circumference, and blood pressure at each visit, and a lipid panel every 2 years (unless if there is significant weight gain).⁸

PCOS consequences on bone mineral density is controversial, partially because of the wide spectrum of clinical presentations. Although hyperandrogenemia and hyperinsulinemia have anabolic effects on bones, the increased inflammation, decreased vitamin D levels osteoprotegerin, aromatase, and growth hormone, as well as the amenorrhea have negative impact on bone formation and reabsorption.⁵⁹ Women with PCOS with ovulatory dysfunction often have acyclic production of 17b-estradiol, with concentrations similar to that of the follicular phase; this is significantly lower than the average 17b-estradiol concentration observed in women with normal menstrual cycle. This stable and suboptimal level of 17b-estradiol negatively affects bone density.⁶⁰

At physiological levels, insulin has a positive impact on the bone; it increases the proliferation of osteoblast and decreases the impact of parathyroid hormone. However, hyperinsulinemia decreases osteoprotegerin and insulin-like growth factors, which may lead to increased bone reabsorption.

Androgens' effect on bones are also complex. Androgens can stimulate osteoblastic cell proliferation but may also indirectly increase inflammatory mediators (interleukin-1β and tumor necrosis factor-α), inhibiting osteoblast differentiation. A recent meta-analysis showed that women with PCOS and BMI <27 kg/m² have decreased levels of the bone formation marker osteocalcin and reduced spinal and femur bone density compared with controls. These findings were not seen in women with PCOS and BMI ≥27 kg/m².⁵⁹

Although androgen deficiency is associated with reduced sexual drive, its impact on women with PCOS is limited. In a recent meta-analysis of 21 observational studies, female sexual dysfunction (FSD) was more prevalent in women with PCOS than without (odd ratio of 1.39). FSD is defined as persistent or recurrent problems with sexual response, desire, orgasm, or pain, which can have adverse effects on quality of life and interpersonal relationship. In the subscale analysis, however, women with PCOS scored lower for pain. There was no significant difference between the two groups regarding the scoring for desire, lubrication, arousal, orgasm, or satisfaction. The exact mechanism is not clear, but was speculated to be related to low self-esteem and emotional distress that might impair sexual function and interpersonal relationships.

In an observational study of 72 women with PCOS and androgen excess treated with oral contraceptive pills, there was significant improvement in dyspareunia, orgasm, and satisfaction at 6 months. More research is required to confirm these findings.⁶¹

Another area of controversy involves the overlap of autism with PCOS and other conditions associated with hyperandrogenemia. A recent large systematic review from low-quality independent cohorts found mixed support for the association between androgen levels in mothers and autistic traits and language ability.⁶² Conversely, elevated prenatal estrogens may be as a risk factor for autism.⁶³ Estrone levels is increased in women with PCOS because of extraglandular aromatization of increased circulating androstenedione levels.⁶⁴

Conclusions

PCOS is an important differential diagnosis of hyperandrogenism to consider in women, with most women presenting with irregular menses, infertility, and hirsutism. The diagnosis should be based on clinical signs (hirsutism, etc.) and/or hyperandrogenemia. Treatment options should be based on targeted treatment, for example, electrolysis and shaving, suppression of testosterone production and/or testosterone receptor blockade, and weight loss. Limited available data indicate that mortality among PCOS patients occurs at a similar rate as in the general population, although there may be decreased longevity related to increased risk of cardiovascular disease. Control of obesity is particularly important for women with PCOS.⁶⁵

Footnotes

Authors' Contributions

S.A.K. wrote the article. A.S.D. provided critical feedback and helped shape it.

Author Disclosure Statement

S.A.K. and A.S.D. have no conflicts of interest.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Abbreviations Used

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Hyperandrogenism in Women with Polycystic Ovarian Syndrome: Pathophysiology and Controversies

Abstract

Introduction

Normal Physiology of Androgens in Women

Diagnosis of PCOS

Clinical and Biochemical Hyperandrogenism

Pathophysiology: Hyperandrogenemia and Hyperinsulinism

Management of Hyperandrogenism

Fertility and PCOS

Controversies

Conclusions

Footnotes

Authors' Contributions

Author Disclosure Statement

Funding Information

Abbreviations Used

References