hirsutism
• It is the most common clinical finding of hyperandrogenemia. It is the development of dark, hard and dense terminal hair on the face (cheek, mustache, beard), chest, between tits, inner thigh, abdomen and lower back areas in androgen-dependent areas (midline) where terminal hair is normally absent in women.
• The most common cause is PCOS. It can also occur due to drugs (testosterone, danazol, anabolic steroids, metoclopramide, methyldopa, phenothiazines, progestins, reserpine).
hypertrichosis
• It is an increase in colorless, thin and sparse terminal hair (forearm, leg, forehead, lanugo, eyebrow, eyelash) that is not androgen dependent.
• It may be an autosomal dominant congenital disorder, as well as in some systemic diseases (anorexia, porphyria, hypothyroidism, malnutrition, dermatomyosis), malignancies (paraneoplastic syndrome) or drug use (androgens, androgenic progesterones, DHEA, acetazolamide, corticosteroids such as hydrocortisone, cyclosporine, interferase, cyclosporine, , minoxidil, phenytoin, streptomycin, heavy metals, methyldopa, penicillamine, psoralen, phenothiazine, reserpine, valproic acid) may occur.
Although it is written in one of the reference books that hypothyroidism causes hypertrichosis; another book states that hyperthyroidism causes hypertrichosis (probably due to an editorial error).
Virilization
• It is masculinization. Patients experience increased muscle mass, deepening of the voice, clitoromegaly, acne, androgenic alopecia, and signs of defeminization (breast atrophy, loss of feminine obesity).
• Although hirsutism accompanies virilism; virilism presents with a much more severe androgenic stimulus than hirsutism (ovarian tumors, adrenal tumors or Cushing's syndrome). Therefore, the table is developing rapidly.
hyperandrogenism
• Increased androgenic activity in the body is called hyperandrogenism.
• Hyperandrogenemia is a picture of hyperandrogenism caused by elevated plasma or serum androgen concentrations. Hyperandrogenism is most commonly manifested as hirsutism.
Hyperandrogenism mainly develops in three ways:
ovarian origin
► It constitutes 80% of hyperandrogenisms. It is often associated with anovulation (PCOS). Testosterone rises in serum.
adrenal origin
► It constitutes 1-5% of hyperandrogenisms. DHEA-S is high in serum.
Peripheral origin (idiopathic)
► They are responsible for 15-30% of hyperandrogenisms and there is increased peripheral sensitivity. In this group, which is also considered as idiopathic, the conversion of testosterone to DHT increased due to increased activity of Sa-reductase enzyme in the periphery, that is, in the target tissue.
► DHEAS and testosterone level in serum is normal; because there is only the conversion of testosterone to the more potent DHT
► In these cases, the level of 3a androstenediol glucuronide, the metabolite of DHT, increased in the serum.
► Menstrual cycles are regular.
etiology
Ovarian Causes
non-neoplastic ovarian causes
PCOS (The most common cause of hyperandrogenism and hirsutism.)
0 Stromal hyperplasia
0 Stromal hyperthecosis
neoplastic ovarian causes
Functional (The most common androgen producing tumors are ovarian neoplasms.)
- Sertoli-Leydig cell tumor (most common virilizing tumor in reproductive age), Leydig cell tumor, steroid cell tumor, gynandroblastoma, gonadoblastoma, thecoma, granulosa cell tumor, sex cord stromal tumors with annular tubules, sclerosing stromal tumors
Nan-Functional
- Krukenberg tumor, mucinous cystadenoma, Brenner tumor, serous cystadenoma, endodermal sinus tumor, benign cystic teratoma (dermoid cyst), dysgerminoma
Pregnancy-related causes
0 Theca-lutein cysts
0 Pregnancy luteoma
Adrenaline Causes
► Late-onset congenital adrenal hyperplasia
► Adrenal tumors (The most common virilizing adrenal neoplasia is adrenal carcinoma.)
► Cushing's syndrome
Idiopathic (Peripheral) Iatrogenic Causes (drugs)
Other Causes
► Hyperprolactinemia
► Hypothyroidism
► Acromegaly
Diagnosis of Hirsutism
• The scoring system used in hirsutism is Ferriman-Gallway. In this system, abnormal hair distribution is evaluated in 9 body regions and a score between 0-4 is given to each region according to the severity of hair growth. In this scoring system, more than 8 points is considered hirsutism. Scoring is used both to determine the degree of hirsutism and to evaluate the response to treatment.
• Patients diagnosed with hirsutism should first measure free testosterone (depending on total testosterone, SHBG and albumin). Total testosterone level is not a reliable indicator of bioactive testosterone, but measurement of total testosterone may be recommended in severe hyperandrogenism (such as virilization) and androgen-producing neoplasms.
• Also when needed for late adrenal hyperplasia the morning follicular phase 17-OH progesterone level increases.
• The DHEA-S measurement has limited diagnostic value and can be used to screen for androgen-secreting adrenocortical tumors (> 800 µg/dl).
• It is meaningful to measure TSH and prolactin in those with amenorrhea or menstrual irregularities.
• When Cushing's syndrome is suspected, 24-hour urine cortisol level measurement (the most specific and sensitive test) or dexamethasone suppression test should be performed.
• Conjugated androgen testing is not recommended (eg androstenediol, androsterone)
Treatment of hirsutism
• In patients presenting with the complaint of hirsutism, the source of the increased androgen load in the patient must be accurately determined in order to initiate appropriate treatment. The treatment given will be directed towards the androgen source.
• All antiandrogenic drugs are teratogenic and can cause feminization of the external genitalia of the male fetus. For this reason, they are often combined with OCS.
|
Treatment
of hyperandrogenism |
|
|
Type of Treatment |
Specific Agents |
|
hormonal suppression |
Combined oral contraceptives |
|
Antiandrogens |
Spironolactone |
|
Steroidogenesis enzyme inhibitors |
ketoconazole |
|
5 alpha reductase enzyme inhibitors |
Finasteride |
Combined oral contraceptives
► Decreases ovarian and adrenal androgen production.
Mechanisms of action
1. They reduce the production of androgens from the ovary by suppressing LH with the progesterone they contain.
2. They reduce free testosterone by increasing the level of SHBG with the estrogen they contain.
3. They reduce circulating androgen levels, including DHEA-S.
4. By inhibiting 5 alpha reductase, it prevents the conversion of T to DHT in the periphery.
► Androgenic potential of progesterones in COC structure affects treatment. Norgestrel, norethindrone and norethindrone acetate are not preferred in treatment because their androgenic effects are dominant; Desogestrel, gestodene, norgestimate and drospirenone should be the first choice in treatment because their androgenic effects are low.
The efficacy of COCs alone in the treatment of hirsutism is very low (<10%). Therefore, an antiandrogenic agent should be added to COCs for an effective treatment. The most effective hirsutism
The treatment is a combination of COC + spiranolactone.
Medroxyprogesterone acetate
► In oral or intramuscular use, it suppresses the release of LH and FSH by suppressing the release of GnRH in the hypothalamus. Thus, androgen and estrogen secretion from the ovary decreases. Although there is a slight decrease in SHBG, both total and free testosterone are significantly reduced.
GnRH analogs
► GnRH analogs inhibit ovarian steroidogenesis by suppressing gonadotropin release; however, it has no effect on adrenal androgen production. Therefore, it distinguishes ovarian hyperandrogenemia from adrenal hyperandrogenemia.
► Monthly depot administration treats both idiopathic hirsutism and hirsutism in PCOS.
Glucocorticoids
► By suppressing the release of ACTH, they reduce the production of androgens from the adrenal. It is used only in PCOS patients with adrenal or mixed adrenal+ovarian hyperandrogenism.
► Since the glucocorticoid effect of dexamethasone is 40 times greater than that of cortisol and it has no mineralocorticoid effect, it becomes the first preferred agent. The adrenal suppression effect should not be forgotten in long-term use.
Spironolactone
► Spironolactone, an aldosterone antagonist, is a potent potassium-sparing diuretic. Inhibits ovarian and adrenal androgen synthesis. Although the serum testosterone level decreases with treatment, both in idiopathic cases and in PCOS, the decrease is much more pronounced in idiopathic cases. SHBG level does not change.
Effect Mechanisms
1. Competitive inhibition of DHT at the receptor level
2. Decrease in CYP-17 enzymes and suppression of testosterone synthesis
3. Enhancement of androgen catabolism (accelerates the peripheral conversion of testosterone to estrogen)
4. Inhibition of 5 a reductase in the skin
► May cause abnormal uterine bleeding (metrorrhagia) (the most common side effect). Because of their synergistic effects, they are usually given in addition to COCs to take advantage of their peripheral effects. Theoretically, contraception is necessary during its use, as it can feminize the male fetus in pregnant women.
cyproterone acetate
► Cyproterone acetate; It is a synthetic derivative of 17-OHP, an antiandrogenic progestin.
Effect Mechanisms
1. Competitive inhibition of T and DHT at the level of androgen receptors (primary mechanism of action)
2. Increased clearance of androgens by induction of hepatic enzymes
3. Reduction of DHEA-5 level with mild glucocorticoid effect
4. Reduces circulating androgen and LH levels.
flutamide
► It is a pure nonsteroidal antiandrogen. Its mechanism of action is inhibition of androgens binding to nuclear receptors in target tissues. It also slightly suppresses testosterone biosynthesis.
► It is effective in acne, seborrhea, hair loss and hirsutism. Theoretically, contraception is necessary during its use, as it can feminize the male fetus in pregnant women. It also has hepatotoxic side effects.
ketoconazole
► It prevents the synthesis of adrenal and ovarian androgens by inhibiting the cytochromal enzyme (17-20 lyase) involved in Steroidogenesis. Androstenedione, testosterone and free testosterone significantly reduces.
Finasteride
► It is a specific inhibitor of 5a-reductase enzyme. It is used for male pattern hair loss in women. In the use of finasteride, ovulation is not suppressed and therefore menstrual irregularities are not observed. Theoretically, contraception is necessary during its use, as it can feminize the male fetus in pregnant women.
Eflornithine hydrochloride (difluoromethylornithine)
► It inhibits cell growth by irreversibly inhibiting ornithine decarboxylase. It is used topically on the face and chin. It is effective after 4-8 weeks and returns to its original state after 8 weeks.
Chronic Anovulation
• The presence of an intact hypothalamo-pituitary-ovarian axis is necessary for regular ovulation in women. Failure in any part of this axis causes anovulation.
In cases with chronic anovulation, hypothalamo-hypophyseal disorders, hypothyroidism, anorexia nervosa, PCOS and primary ovarian failure should be evaluated in the differential diagnosis. Serum FSH, PRL and TSH levels are the tests that should be absolutely checked in the differential diagnosis.
Long-term complications of chronic anovulation
1. Infertility
2. Menstrual irregularities (oligomenorrhea - amenorrhea - DUB)
3. Hirsutism, alopecia, acne
4. Increased risk of endometrial cancer
5. Increased risk of cardiovascular disease
6. Increased risk of insulin resistance and diabetes