Hyperandrogenism in Women

Hyperandrogenism is any state with excess production of "male" hormones, although these hormones are normally found in women at lower levels. The most clinically relevant hormone in hyperandrogenism is testosterone , which is peripherally converted to dihydrotestosterone (DHT), its biologically active form.

The most common symptom of hyperandrogenism in women is hirsutism, and the most common cause is polycystic ovary syndrome (PCOS). The approach to hyperandrogenism in women differs depending on the stage of life.

This article will serve as a concise review of hyperandrogenism in women at various periods of adult life.

In women, the two sources of androgens during the reproductive years are the adrenal glands and the ovaries.

33% of circulating testosterone is produced by theca cells of the ovaries. The remaining testosterone is derived from androstenedione (A4), which is produced in both the ovaries and adrenal glands. Testosterone is then converted by 5-alpha reductase to DHT both in the granulosa cell of the ovary and in peripheral tissues such as the skin.

A4 and dehydroepiandrosterone (DHEA) are secreted by the ovaries and adrenal glands. Dehydroepiandrosterone sulfate ( DHEA-S) is only produced in the zona reticularis of the adrenal gland. DHEA is converted to A4. Adrenal androgen production is under the control of adrenocorticotrophic hormone (ACTH), while ovarian androgen production is under the control of luteinizing hormone (LH).

DHEA, DHEA-S and A4 are considered pre-androgens since their action on the androgen receptor is much less potent than testosterone. In women, they may play a role in hyperandrogenic symptoms and signs because overall testosterone levels are relatively low.

Androgens have direct effects on reproduction through the androgen receptor and indirect effects through conversion to estrogens. The androgen receptor is present in cells along the hypothalamic-pituitary-ovarian axis. Therefore, high androgen levels can suppress hypothalamic and pituitary secretion of GnRH, LH, and follicle-stimulating hormone (FSH) directly and through aromatization to estradiol.

PCOS is by far the most common cause of hyperandrogenism in women, so most of the genetic data on female hyperandrogenism comes from PCOS studies.

It is an inherited polygenic disorder with multiple risk factors that contribute to the disease. However, the exact underlying mechanism by which it influences androgen concentrations and actions is unclear.

The three most important aspects when taking a medical history in women with hyperandrogenism are age, ethnic origin, and duration of symptoms. The main differential diagnoses change depending on these characteristics.

> Age

Premenopausal women are more likely to have polycystic ovary syndrome or nonclassical congenital adrenal hyperplasia (NCCAH). The main diagnoses would change to ovarian hyperthecosis and androgen-producing tumors in postmenopausal women. If the woman is pregnant, gestational hyperandrogenism would be the likely culprit.

> Ethnicity

Women of Mediterranean, Middle Eastern, South Asian, and Hispanic ethnicities have higher cut points for hirsutism rating scales compared with East Asians and Caucasians of Northern European descent.

> Duration of symptoms

The rapid onset (over months) of increased hair growth is concerning for an androgen-producing tumor compared to PCOS. The most common symptoms of hyperandrogenism in women are the following:

 -  Hirsutism: defined as the growth of male-pattern terminal hair in a woman. Both the location of the hair growth that bothers the woman and the type of hair development influence the treatment plan.

 -  Alopecia: The typical pattern of hair loss in women with hyperandrogenism follows a male model with thinning/vertex baldness (male pattern hair loss or MPHL). MPHL or androgenic alopecia is commonly associated with elevated levels of circulating androgens. Female pattern hair loss (FPHL) usually occurs on the central scalp with preservation of the frontal hairline.

 -  Acne: sebum formation is favored in the presence of a proandrogenic environment.

 -  Oligomenorrhea/Amenorrhea: Documentation of age at menarche, menstrual cycle history, and use of any hormonal contraceptives are important aspects to further elucidate the underlying etiology of hyperandrogenism. Symptoms and signs of virilization are more likely to indicate an ovarian or adrenal tumor. These signs include deepening of the voice, clitoromegaly, and increased muscle mass.

The most useful laboratory test is the total testosterone concentration. The test method, however, influences the precision of this measurement. Liquid chromatography/mass spectrometry (LC-MS/MS) is the most reliable method to quantify excess androgens in women.

Measurement of total testosterone by direct radioimmunoassay (RIA) is the most widely available method. Free testosterone is strongly correlated with hyperandrogenism. However, its measurement is riddled with inaccuracies.

It should be noted that laboratory tests should not be performed until at least 3 months after stopping hormonal contraception of any type and in the absence of progestin-coated IUDs. The hormones will suppress endogenous androgens and make measurements inaccurate for clinical diagnostic purposes.

Low levels of sex hormone binding globulin (SHBG) can be used as a surrogate marker for higher levels of free testosterone.

> Images

If physical examination reveals virilization or laboratory measurements show severe biochemical androgen excess (total testosterone by LC/MS -150 ng/dL in a premenopausal woman or -64 ng/dL in a postmenopausal woman), pelvic imaging should be performed. be the next step in the evaluation.

Due to lower cost, transvaginal color Doppler ultrasonography should be the first line of imaging. However, ovarian tumors are generally small in size (Leydig cell tumors <3 cm) and isoechoic. They are easily missed with transabdominal ultrasound.

MRI would be the next best step if the pelvic ultrasound is negative. 18 fluorodeoxyglucose (18FDG)-PET is generally reserved for selected cases.

When pelvic imaging is negative or if androgen levels suggest an adrenal etiology (DHEA-S >700 µg/dL), adrenal computed tomography (CT) would be the next step. Adrenal CT should be performed with and without contrast in order to calculate Hounsfield units and absolute and relative washout. If CT is contraindicated, MRI with chemical shift measurement can be performed. 18FDG-PET/CT may also be considered second line in selected cases.

The main differential diagnoses differ depending on the woman’s stage of life.

We list the 3 most common diagnoses in premenopausal and postmenopausal women. Additionally, gestational hyperandrogenism is briefly explored.

> Premenopausal hyperandrogenism

 -  Polycystic ovary syndrome: PCOS is the most common endocrine disorder in women of reproductive age and affects approximately 10% of the population. Two of the three Rotterdam criteria are required to achieve the diagnosis: (1) oligomenorrhea/amenorrhea, (2) clinical or biochemical hyperandrogenism, and/or (3) polycystic ovaries on ultrasound, which is defined as 20 or more antral follicles and /or ovarian volume greater than 10 cm3.

 -  Idiopathic hirsutism: When no abnormalities are found in the investigation, that is, elevated testosterone or DHEA-S and normal ovaries in the ultrasound in a woman under 40 years of age and who is not taking hormonal contraceptives and there are no menstrual disorders, the procedure is performed. diagnosis of idiopathic hirsutism.

 -  Non-classical congenital adrenal hyperplasia: NCCAH is due to 21-hydroxylase (P450c21) deficiency leading to an increase in the 17-hydroxyprogesterone precursor available for the androgen pathway with increased production of androstenedione and testosterone. Unlike the classical form, NCCAH rarely presents with cortisol deficiency and therefore glucocorticoid replacement or ACTH suppression is not needed unless fertility is desired.

> Postmenopausal hyperandrogenism

 -  Ovarian hyperthecosis: it is a histological diagnosis observed when there is the presence of nests of luteinized theca cells throughout the ovarian stroma. Postmenopausal women present with slowly progressive onset symptoms of hyperandrogenism. In severe cases, virilization may occur. Typical signs of insulin resistance are usually present (acanthosis nigricans, skin tags, central obesity).

 -  Ovarian and adrenal neoplasms: Androgen-producing tumors are more common in postmenopausal women. Most ovarian sources are benign, while adrenal tumors can be benign or malignant. Women present with rapid and progressive symptoms of hyperandrogenism, often with virilization. Surgical resection results in rapid resolution of symptoms.

 -  Iatrogenic hyperandrogenism: Androgens, including DHEA, are often prescribed to treat postmenopausal symptoms. Currently available testosterone replacements were developed for male hypogonadism, but may be a cause of hyperandrogenism in women exposed to their partner’s topical testosterone.

> Gestational hyperandrogenism

Hyperandrogenism in pregnancy is extremely rare. During normal pregnancy, testosterone and A4 concentrations increase progressively with each trimester, returning to initial concentrations after delivery.

Rarely, a pregnancy luteoma, the physiological remnant of the corpus luteum from the menstrual cycle of conception, produces elevated levels of testosterone and results in hyperandrogenism.

The goals of treatment are twofold: (1) identify and surgically treat severe virilization and (2) decrease any perceived symptoms/signs of hyperandrogenism.

Ovarian and adrenal tumors should undergo complete surgical resection if possible. Bilateral oophorectomy is the treatment of choice for ovarian hyperthecosis. If a tumor is not identified in postmenopausal women, bilateral oophorectomy should be performed, given the high probability of ovarian origin. In premenopausal women, fertility-sparing cytoreductive surgery should be considered.

For adrenal tumors, nonsurgical techniques may be used if surgery is contraindicated or not desired. Radiofrequency ablation and CT-guided cryoablation have been used in functional adrenal adenomas with similar results compared to surgical resection.

> Medical management

Lifestyle: In obese women with PCOS, weight loss produces a small decrease in testosterone as measured by the free androgen index. It has limited impact on improving hyperandrogenism and should not be the only management strategy.

Oral contraceptives : Oral contraceptives containing ethinyl estradiol (EE) suppress LH production and increase SHBG concentrations, resulting in decreased ovarian androgen production and decreased free testosterone concentrations, respectively.

Antiandrogens: After 6 months of oral contraceptive use, an antiandrogen can be added to improve symptoms of hyperandrogenism.

Spironolactone: It is effective in reducing hirsutism scores. It is contraindicated in pregnancy due to blocking the action of androgens.

Finasteride: decreases local DHT levels in hair follicles with effects comparable to other antiandrogens. The effect depends on the dose.

Cyproterone acetate – is a competitive androgen receptor inhibitor and is commonly used outside the United States. It is available in combination with EE in the form of combined oral contraceptive pills. It presents the risk of venous thromboembolism.

Local/topical treatment : If medical management is contraindicated or symptoms are not concerning enough for the woman to warrant systemic therapy, local treatment options should be discussed. Direct hair removal can be used by shaving, bleaching, chemical creams, photoepilation or electrolysis.

Glucocorticoids: In classic congenital 21-hydroxylase adrenal hyperplasia, glucocorticoids are effective in suppressing ACTH-stimulated adrenal androgen production.

GnRH agonists: they are equally effective as oral contraceptives in reducing hirsutism. Its use should be reserved for rare cases of virilization that are not amenable to other therapies.

Medications that reduce insulin levels or improve insulin action: were no more effective than placebo in treating hyperandrogenism in PCOS. Therefore, metformin should be reserved for the treatment of prediabetes or type 2 diabetes in women with PCOS, since it is not as effective as other drugs due to aesthetic problems or for uterine protection in case of irregular menstruations.