Androgen Excess - 2024 PDF

Hyperandrogenism Disorders Dr.Khalida Hassan Muho Specialist OB\GYN Hyperandrogenism Disorders Hyperandrogenism is the clinical manifestation of elevated levels of male hormones in women. features may range from mild unwanted excess hair growth and acne to alopecia, more extensive hi...

Hyperandrogenism Disorders Dr.Khalida Hassan Muho Specialist OB\GYN Hyperandrogenism Disorders Hyperandrogenism is the clinical manifestation of elevated levels of male hormones in women. features may range from mild unwanted excess hair growth and acne to alopecia, more extensive hirsutism ,and masculinization and virilization. Hirsutism defined as excessive terminal hair appearing in a male-type pattern, represents exposure of hair follicles to androgen excess either from a systemic origin and/or the local conversion of testosterone to the more potent dihydrotestosterone (DHT) by 5α- reductase in the hair follicle itself.  Virilization (masculinization) refers to the acquisition of male characteristics i.e.,  Temporal balding,  deepening of the voice,  enlargement of the clitoris.  defeminization or the loss of female body fat distribution (gluteofemoral fat deposits) and decreased breast size In females, it usually results from excessive male hormone production or exogenous hormone use.. Androgens in women are normally produced in the ovaries and the adrenal glands. Therefore, hyperandrogenic disorders may be divided into nonneoplastic and neoplastic disorders of the adrenal glands or ovaries NORMAL ANDROGEN METABOLISM The formation of androgens results from the metabolism of cholesterol via the Δ5 and Δ4 pathways (see Figure 1 ). The stimulus for ovarian androgen production is LH. Approximately one-half of serum androstenedione originates from the ovaries, whereas the other half arises from the adrenal glands. Approximately 50% of testosterone arises from peripheral conversion of androstenedione, whereas 25% is secreted by the ovaries and an additional 25% by the adrenal glands. Dehydroepiandrosterone (DHEA) and its sulfate DHEA-S are primarily products of the adrenal glands and serve as markers for the secretion of adrenal androgens. Most circulating androgens are bound to proteins, such as albumin and sex hormone– binding globulin (SHBG). In the bound form, androgens are The free fraction (that which is unbound to SHBG or albumin and is available for target tissue activity) represents only about 1-2% of total circulating testosterone. When androgens reach a target tissue, they are further metabolized, which results in more potent intracellular hormones. Testosterone is converted (via 5α-reductase) to DHT, which possesses greater biologic potency. The skin, particularly its pilosebaceous unit (PSU), is capable of this conversion and is the reason why hirsutism can be accompanied by oily skin and acne. Alternatively, testosterone may be aromatized to estrogen, thereby modifying its action. Unlike testosterone, DHT is a potent, nonaromatizable androgen that cannot be converted to estrogen. Fig 1 ADRENAL DISORDERS Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH) is a general term used to describe a group of disorders that arise from inborn glandular enzyme defects that cause overproduction of the immediate steroid precursor of the specific enzyme deficiency. The most common cause of CAH is 21-hydroxylase deficiency, an autosomal recessive disorder that exhibits a spectrum of severity, ranging from the severe salt-wasting form, to simple virilizing CAH, to nonclassic CAH Both salt-wasting and simple virilizing CAH are called classic because symptoms (e.g., salt loss or ambiguous genitalia in female newborns) are present at birth or shortly thereafter. Alternatively, the nonclassic form (also called late-onset CAH) presents later in life, generally at the time of puberty or later. These patients do not present with genital abnormalities, but rather develop hirsutism, acne, and menstrual and/or ovulatory irregularities. Because 21-hydroxylase is responsible for the conversion of 17- hydroxyprogesterone to 11-deoxycortisol (compound S), 21-hydroxylase deficiency causes excessive accumulation of 17- hydroxyprogesterone as the immediate steroid precursor for this enzyme. Consequently, 21-hydroxylase deficiency is characterized by an elevated serum 17-hydroxyprogesterone level as well as increases in its Δ4 metabolites 4 androstenedione and testosterone (see Figure1) The disease is inherited as an autosomal recessive trait. In patients with a positive family history and in ethnic groups with a high risk for nonclassic CAH (e.g., Ashkenazi Jews, with a prevalence of 1 in 27; Hispanics, with a prevalence of 1 in 40; and Slavs, with a prevalence of 1 in 50), this enzyme deficiency can be excluded by obtaining a follicular (preovulatory) phase serum 17- hydroxyprogesterone level, preferably in the morning. A level less than 2 ng/mL rules out late-onset CAH. Cushing Syndrome Another major adrenal disorder that leads to excessive androgen production is Cushing syndrome or persistent hypercortisolism. Characteristic signs of Cushing syndrome include obesity; increased fat over the face (moon facies), trunk, and cervicodorsal as well as supraclavicular regions; hypertension; easy bruising resulting from thinning of the skin; impaired glucose tolerance; muscle wasting of the upper legs and arms; osteoporosis; and purple abdominal striae. Other manifestations include hirsutism, acne, and irregular menses. Mental disturbances include excessive euphoria, irritability, insomnia, and depression. The depression may occur because of excess cortisol action on the CNS limbic system. Cushing syndrome may arise from a cortisol-producing tumor of the adrenal glands or from an ACTH-producing pituitary adenoma (called Cushing disease). These disorders are rare causes of androgen excess in women. Adrenal Neoplasms Adrenal tumors causing hyperandrogenism alone without evidence of glucocorticoid excess are very rare. More commonly, adrenal tumors produce large amounts of both glucocorticoids and androgens, with the predominant adrenal androgen being DHEA-S. OVARIAN DISORDERS  Polycystic Ovarian Syndrome  Hyperandrogenic Insulin Resistance and Acanthosis Nigricans Syndrome(HAIR- AN) is an inherited hyperandrogenic disorder of severe insulin resistance and is distinct from PCOS. HAIR-AN syndrome is characterized by extremely high circulating levels of insulin (>80 μU/mL basally and/or >500 μU/mLfollowing an oral glucose challenge) Because insulin is also a mitogenic hormone, these extremely elevated insulin levels induce hyperplasia of the basal layers of the epidermal skin, leading to acanthosis nigricans, a velvety, hyperpigmented change in the creased areas of the skin. because of the effect of hyperinsulinemia on ovarian theca cells, the ovaries of many patients with the HAIR-AN syndrome develop hyperthecosis. Patients with HAIR-AN syndrome can be severely hyperandrogenic and present with In addition, these patients are at significant risk for dyslipidemia, type 2 diabetes mellitus, hypertension, and cardiovascular disease These patients are particularly difficult to treat, although the use of long-acting GnRH analogs has been promising.  Ovarian Neoplasms Androgen-producing ovarian tumors are uncommon, occurring in only about 1 in 500 women with hirsutism. Ovarian tumors that produce androgens directly include Sertoli-Leydig cell, hilus cell, and lipoid cell tumors. Nevertheless, any large ovarian tumor (i.e., cystic teratomas, Brenner tumors, serous cystadenomas, and Krukenberg tumors) can produce androgens indirectly by causing hyperplasia of the surrounding normal stroma.  IDIOPATHIC HIRSUTISM Some women exhibit mild to moderate hirsutism with normal ovulatory function and circulating androgen levels, a condition referred to as idiopathic hirsutism. This scenario may occur as a result of increased conversion of testosterone to the more biologically active DHT in the pilosebaceous units of the skin. Evaluation of patients with signs of hyperandrogenism  history, time of onset of hair growth: PCOS or late-onset CAH often initially appear during puberty and tend to progress slowly throughout adolescence into adulthood. Under these circumstances, the signs of androgen excess develop over the course of several years.. In contrast, neoplastic disorders can occur at any time. They most often arise many years after puberty, and their manifestations appear abruptly.  Velocity of hair growth: 1.Rapid hair growth(neoplasm of ovary or adrenal). 2.Gradual onset of excess hair growth(2-3 years after menarche- PCOS). The presence of hirsutism and oligomenorrhea indicates PCOS in most cases. Physical Examination: 1.Asses degree of hirsutism, by using scale system(Ferriman- Gallwey scoring system). also asses degree of acne, or androgenic alopecia. 2. Approximately half of patients with hyperandrogenic disorders are obese, and many exhibit evidence of acne and hirsutism 3.Patient should be expressly asked about excess facial hair because they may conceal their hirsutism by waxing or electrolysis and be embarrassed to volunteer the information. 4. The thyroid should be palpated for any enlargement, and the breasts should be examined for galactorrhea 5.Evidance of cushingoid features should be noted. 6.Acanthosis nigricans is frequent marker of insulin resistance and hyperinsulinemia. 7.Sign of virilzation (clitoromegally). 8.A bimanual pelvic examination may identify ovarian enlargement. Asymmetrical ovarian enlargement associated with the rapid onset of virilizing signs usually indicates an androgen-producing tumor. LABORATORY EVALUATION circulating total and free testosterone and DHEA-S are elevated in 50-75% of patients with PCOS. Serum levels of DHEA-S above 7000 ng/mL or total testosterone in excess of 200 ng/dL raise suspicion of an adrenal or ovarian androgen-producing tumor, respectively. However, the best predictor of an androgen-secreting neoplasm is virilization, which occurs with 98% of such tumors, regardless of circulating Measuring a basal serum 17- hydroxyprogesterone level is useful to exclude late-onset CAH due to 21- hydroxylase deficiency. A serum 17- hydroxyprogesterone level greater than 2 ng/mL requires an adrenal stimulation test to measure serum 17- hydroxyprogesterone before and 1 hour after intravenous infusion of the ACTH analog cosyntropin. If a 1-hour ACTH- stimulated serum 17- hydroxyprogesterone level exceeds 10 to 15 ng/mL, late-onset CAH is likely and Measurement of serum prolactin and TSH levels excludes hyperprolactinemia, with or without thyroid dysfunction. When Cushing syndrome is suspected, either a 24-hour measurement for free urinary cortisol or an overnight dexamethasone suppression test should be performed. For the latter test, 1-mg dexamethasone is given orally at bedtime (11:00 pm), and serum cortisol is measured in an 8:00 am fasting specimen. Normal values are less than 5 A pelvic ultrasound should be obtained to exclude any significant ovarian pathology. Androgen-secreting tumors of the adrenal gland can be detected by CT or MRI. A metabolic evaluation should be performed in patients with HAIR-AN syndrome or classic PCOS (particularly in those with a BMI >30 kg/m2, lean with advanced age [>40 years], with a personal history of gestational diabetes, or with a family history of diabetes). Treatment Treatment of hirsutism or virilism is guided by the nature of the underlying disease, the severity of clinical symptoms and signs, and the ultimate desires of the patient. If an ovarian or adrenal neoplasm exists, surgical removal of the tumor is indicated. In premenopausal women, unilateral salpingo- oophorectomy is usually sufficient for an ovarian tumor and preserves future childbearing potential. In postmenopausal women, the treatment is usually a total abdominal hysterectomy and bilateral salpingo-oophorectomy. In patient with Cushing's syndrome ,treatment is surgical removal of the source of excess cortisol or ACTH(adrenal or pituitary tumor).  PCOS is by far the most common ovarian abnormality causing hyperandrogenism, and its management depends on the patient's presentation and desires. The therapy for the hirsutism in PCOS patients is ovarian suppression, which is usually achieved by administration of an estrogen-progestin contraceptive. Oral contraceptive therapy suppresses gonadotropins(LH and FSH), and lowers circulating androgen levels, whereas its Estrogen component stimulates SHBG production, which decreases free testosterone levels. A peripheral antiandrogen can be added to oral contraceptive therapy to treat hirsutism, regardless of the source of the excessive androgen. This therapy also may improve idiopathic hirsutism., An antiandrogen is combined with an oral contraceptive for synergism and to prevent conception because an antiandrogen would block normal sexual differentiation in a male fetus if used during pregnancy. The antiandrogen most commonly used to treat hirsutism in the United States is spironolactone. This aldosterone antagonist competes for testosterone-binding sites, thereby exerting a direct antiandrogenic effect in target tissues spironolactone interferes with steroid enzymes and decreases testosterone production. Because this medication opposes the action of aldosterone, serum potassium levels may rise and  Other drugs that block the binding of androgen to its receptor include flutamide and cyproterone acetate , whereas finasteride blocks the conversion of testosteron to its more potent metabolite, dihydrotestosterone.it may take up to 6 months to begin to observe a cosmetic improvement in hirsutism,and maximum effect may not be seen for up to 2 years. Eflornithine hydrochloride cream, an irreversible inhibitor of epidermal androgenic activity, can be applied topically to treat facial hirsutism. It requires twice-daily application for up to 8 weeks for improvement to be seen and may be associated with rash, stinging, redness, and acne. Suppression of excessive androgenic action generally diminishes further hair growth, but does not cause disappearance of existing hair. To obtain good cosmetic results, some local hair removal is usually required in addition to medical therapy. Mechanical methods of hair removal include shaving, depilatory creams, electrolysis, and laser therapy and/or intense pulsed light. Plucking of individual hairs should be discouraged because of discomfort and the risks of scarring and folliculitis. Regardless of the method of hair removal used, pharmacologic therapy should be continued in women with hyperandrogenemia to minimize hair regrowth. All patients with PCOS who have chronic anovulation are at increased risk of developing menstrual irregularity. With tonic estrogen production without progesterone exposure, anovulatory women with PCOS also are at increased risk of developing endometrial hyperplasia as a precursor of endometrial cancer. Medical management of abnormal vaginal bleeding or endometrial hyperplasia consists of estrogen-progestin oral contraceptives, cyclic or continuous , 100 to 300 mg of micronized progesterone one to three times daily, or 2.5 to 10 mg of norethindrone acetate daily), or a levonorgestrel- releasing intrauterine system (Mirena). Patients with adrenal hyperandrogenism, including late- onset CAH, can be treated with glucocorticoids (e.g., 0.25-mg dexamethasone every other day at bedtime). Many of these women, like those with PCOS, also require suppression of ovarian androgen secretion using combination oral contraceptives and antiandrogens. THANK YOU