Week 4: Reproductive pharmacology: Androgens Flashcards
Stuff not discussed in class
Pharmacologic uses of testosterone
- Anabolic effects
- Androgenic effects (in the treatment of testosterone deficiency
Clinical uses of testosterone
- The primary clinical use of the androgens is for replacement therapy in hypogonadism
- Androgens have also been used to stimulate red blood cell production in certain anemias and to promote weight gain in patients with wasting syndromes (eg AIDS patients)
- The anabolic effects have been exploited illicitly by athletes to increase muscle bulk and strength
Androgen toxicities
- Use of androgens by females results in virilization (hirsutism, enlarged clitoris, deepened voice) and menstrual irregularity
- In women who are pregnant with a female fetus, exogenous androgens can cause virilization of the fetus’ external genitalia
- Excessive doses in men can result in feminization (gynecomastia, testicular shrinkage, infertility) as a result of feedback inhibition of the pituitary and conversion of the exogenous androgens to estrogens
- In both sexes, high doses of anabolic steroids can cause cholestatic jaundice, elevation of liver enzyme levels and possibly hepatocellular carcinoma
List of antiandrogens
- Receptor antagonists (flutamide)
- 5α-reductase inhibitors (finasteride)
- Synthesis inhibitors (ketoconazole)
- Other (GnRH agonist, combined oral contraceptives)
Flutamide MOA
flutamide and related drugs are non-steroidal competitive antagonists of androgen receptors
Flutamide clinical uses
used to decrease the action of endogenous androgens in patients with prostate carcinoma
Spironolactone MOA
A drug that is primarily used as a potassium-sparing diuretic but it also inhibits androgen receptors
Spironolactone clinical uses
Primarily used as a Potassium-sparing diuretic but also inhibits androgen receptors and is used in the treatment of hirsutism in women
5α-reductase inhibitors MOA
- Testosterone is converted to 5α-reductase
- Some tissues, notably prostate cells and hair follicles depend on DHT rather than testosterone for androgenic stimulation
5α-reductase inhibitor prototype
Finasteride
Finasteride MOA
- 5α-reducatase inhibitor
- 5α-reducatase converts testosterone to DHT
- Finasteride inhibits this
Clinical uses of Finasteride
- benign prostatic hyperplasia
- at lower dose: prevent hair loss in men
Finasteride adverse effects
Because the drug does not interfere with the action of testosterone, is is less likely than other antiandorgens to cause impotence, infertility and loss of libido
Inhibitors of steroid synthesis prototype
Ketoconazole
What is ketoconazole?
- an antifungal drug, inhibits gonadal and adrenal steroid synthesis
- The drug has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic prostate cancer
Clinical uses of Ketoconazole
- an antifungal drug, inhibits gonadal and adrenal steroid synthesis
- The drug has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic prostate cancer
GnRH analogs and antagonists as antiandrogens
Combined hormonal contraceptives as antiandrogens
What are the sources and types of androgens in women?
Describe androgen metabolism in women
- In healthy women, 80% of testosterone is bound to sex hormone binding globulin (SHBG), 19% is bound to albumin and 1% circulates freely in the blood stream
- The remaining androgens, DHEAS, DHEA and androstenedione are almost entirely bound to albumin
- Unlike SHBG; albumin has a low affinity for sex hormones, so the albumin-bound androgens are readily available to tissues
What is androgen excess?
- Androgen excess is a common feature of polycystic ovary syndrome (PCOS), which is also the most common cause of anovulatory infertility
- The ovarian theca cells increase their ovarian androgen production under the stimulatory activity of the raised LH levels, and in many cases, raised insulin levels
- Androgen excess affects mainly the pilosebaceous unit (PSU) and the reproductive system
- The PSU secretes sebum and is the unit from which hair grows
- Hirsutism affects 70-80% of women with androgen excess
- Acne vulgaris can be aggravated or initiated by increased androgen levels
- Hyperinsulinemia due to peripheral insulin resistance is often present in women with PCOS and it promotes hyperandrogenemia through the binding of insulin to the insulin-like growth factor-1 (IGF1) receptor
Etiologies of androgen excess
- Androgen excess can result from ovarian or adrenal tumors
- Other disorders such as Polycystic Ovarian Syndrome, Cushing’s Syndrome (the overproduction of cortisol), hyperprolactinemia and congenital adrenal hyperplasia can cause extra male hormones to be produced
Symptoms of androgen excess in women
- Acne
- Decrease in breast size
- Increase in body hair in a male pattern, such as on the face chin and abdomen
- Lack of menstrual periods (amenorrhea)
- Oily skin
The following may also occur:
- Increase in the size of the clitoris
- deepining of the voice
- Increase in muscle mass
- thinning hair at the front of the scalp on both sides of the head
Androgen excess mortality/morbidity
- Androgen excess is associated with insulin resistance dyslipidemia, hypertension and vascular diseases
- impaired glucose tolerance and type 2 diabetes affect about 40% of women with PCOS
- Women who have anovulatory PCOS have greater cardiovascular risk compared with women who have ovulatory PCOS and idiopathic hyperandrogenism
- Androgen-secreting tumors are rare and about 30% of them are malignant
Pharmacotherapy of androgen excess
Medical treatment of androgen excess is aimed at lowering ovarian or adrenal androgen production, reducing the free-androgen level and blocking the peripheral androgen action. however, patients with androgen excess typically seek medical attention for the treatment of primary symptoms such as hirsutism, acne and menstrual disorders
Methods to treat hirsutism
- best treated by a combination of mechanical and chemical methods
- Mechanical methods remove hair immediately
- chemical methods prevent further differentiation of vellus to terminal hairs
Methods of treating PCOS associated with insulin resistance
can be treated with metformin and/or an OC with or without an added anti-androgen (spironolactone), PCOS not associated with insulin resistance is best treated with an OC with or without added spironolactone
Methods to treat acne by androgen excess
Acne treatment is aimed at decreasing skin sloughing and proliferation of P acnes through the use of topical and systemic agents
Suppression of androgen production decreases production of sebum and reduces acne
Oral contraceptives for androgen excess
Considerations of using antiandrogens for treating androgen excess
- Antiandrogens have teratogenic potential so they should be used with adequate contraception in women of reproductive age
which antiandrogens can be used to treat hirsutism?
- Flutamide is more effective than spironolactone for treating hirsutism, but flutamide is associated with frequent side-effects and low long-term compliance
- Finasteride inhibits only the type 2 isoenzyme of 5α-reductase and thus the effect against hirsutism is partial (FDA has not approved Finasteride for the treatment of hirsutism)
Considerations of GnRH antagonists for the treatment of androgen excess
these agents suppress pituitary LH and FSH secretion, suppres ovarian hormone secretion to a greater degree than COCs
Significant osteoporosis may occur if treatment lasts longer than 6 months; in these cases, estrogen add back with HRT or COC pills should be given
Some GnRH antagonists for androgen excess
- Leuprolide acetate (Lupron, Lupron Depot)
- Nafarelin acetate (Synarel)
MOA Glucocorticoids to treat androgen excess
- Adrenal hyperandrogenism responds well to low-dose glucocorticoid therapy with dexamethasone or prednisolone
- these agents are used with variable success in women with adrenal hirsutism and idiopathic adrenal hyperandrogenism
Some Glucocorticoids to treat androgen excess
- Dexamethasone
- Prednisone
MOA of insulin-sensitizing drugs for treating androgen excess
- Hyperinsulinemia has been shown to increase ovarian androgen production and decrease SHBG production
- Consequently, reducing insulin levels with insulin-sensitizing agents such as metformin should lower total and free androgen levels
- However, the effects on hirsutism are not clearly better than if OCs are used
What is hyperinsulinaemic androgen excess?
hyperinsulinaemic androgen excess is the most common cause of hirsutism, acne, seborrhoea and menstrual irregularity in adolescent girls and young women
What is the most common cause of hirsutism, acne, seborrhoea and menstrual irregularity in adolescent girls and young women?
hyperinsulinaemic androgen excess
Pathophysiology of hyperinsulinaemic androgen excess
- Vulnerability to hyperinsulinemaemic androgen excess is adolescence is increased by prenatal growth restraint
- In humans, prenatal androgen excess does not seem to be a major contributor to the development of adolescent androgen excess
- However, familial clustering of ovarian androgen excess is well-documented, and relatives of girls with precocious pubarche are at an increased risk of androgen excess, impaired glucose tolerance, type 2 diabetes mellitus (T2DM), dyslipidemia and gestational Diabetes Mellitus
- Hyperinsulinemia and impaired glucose tolerance occur across the spectrum of BMI in adolescent girls with androgen excess
Treatment of hyperinsulinaemic androgen excess in adolescent girls
- No approved therapy exists for hyperinsulinaemic androgen excess in adolescent girls
- Traditional first-line treatment with oral contraceptives attenuates the clinical signs of androgen excess, such as hirsutism and acne, by reducing ovarian androgen secretion and eliciting regular pseudomenses as part of anovulatory cycles. This approach has also been recommended for girls who do not need contraception (the majority of girls aged 14-17 years are not sexually active) and even for premenarcheal girls
- oral contraceptives tend to aggravate hyperinsulinemia, especially those that contain cyproterone acetate or drospirenone
Question 1
Case 1 Sarah 16 yo female & question 2
Question 2 based on Sarah
