Male Reproductive Hormones Flashcards
Gonadotropin-Releasing Hormone (GnRH) Mixed Agonists/Antagonists Leuprolide, Goserelin, Buserelin, Nafarelin, Gonadorelin, Histrelin, Triptorelin; —relin (MOA, PK, Pregnancy)
MOA: Depends if dosed continuously or pulsatile. Native GnRH has short half-life, when secreted in pulsatile fashion stimulates LH/FSH release. GnRH analogues with longer half-lives are used to suppress production of sex hormones by desensitizing pituitary gland.
Continuous dosing: SUPPRESSES release of LH/FSH by desensitizing pituitary gland.
Pulsatile dosing: INCREASES release of LH/FSH by mimicking endogenous pulsatile release of GnRH.
PK: Metabolized by hydrolysis via peptidase enzyme
Pregnancy: X
Gonadotropin-Releasing Hormone (GnRH) Mixed Agonists/Antagonists Leuprolide, Goserelin, Buserelin, Nafarelin, Gonadorelin, Histrelin, Triptorelin; —relin (Indications, ADRs, Considerations)
Indications:
Continuous administration—prostate cancer, uterine fibroids, endometrioses, polycystic ovary syndrome (PCOS), precocious puberty
Pulsatile administration—infertility
ADRs:
Common for both dosing regimens—headache, nausea and vomiting, peripheral edema, acne, depression, mood swings, decreased bone mineral density
Continuous administration common—FLARE SYNDROME, sexual dysfunction, and sweating: Flare syndrome at start of continuous treatment that causes hot flashes in men and women.
Rare—Heart failure.
Considerations: Can use androgen/estrogen receptor antagonist to treat flare syndrome at initiation of continuous treatment. May cause hyperglycemic events in diabetes mellitus patients. Contraindicated in pregnancy and breastfeeding.
GnRH agonists used continuously such as, goserelin, is associated with causing a flare syndrome. What causes the flare syndrome? What are the symptoms associated with the flare syndrome? How can the flare syndrome be treated? How long does the flare syndrome need to be treated?
Cause: increased testosterone
Symptoms: flushing, sweating, hot flashes
Treatment: androgen antagonist
Treatment duration: 2 weeks
Gonadotropin-Releasing Hormone (GnRH) Receptor Antagonist - Cetrorelix, Ganirelix, Degarelix; —relix (MOA, PK, Pregnancy, Indications)
MOA: Competitively blocks GnRH receptors in the pituitary, suppressing the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
PK: Dosed daily by injection
Pregnancy: X
Indications: Inhibit premature LH surges in women undergoing controlled ovarian hyperstimulation, endometriosis, menorrhagia, gynecomastia, palliation of metastatic prostate cancer
Gonadotropin-Releasing Hormone (GnRH) Receptor Antagonist - Cetrorelix, Ganirelix, Degarelix; —relix (ADRs and Considerations)
ADRs:
Common—Abdominal pain, menopausal symptoms (hot flashes, osteoporosis), nausea, vomiting, headache
Serious—Immune hypersensitive reaction, ovarian hyperstimulation syndrome. Ganirelix can cause SPONTANEOUS ABORTION.
Considerations: A direct GnRH antagonist has the advantage of avoiding the initial surge of testosterone caused by treatment of continuous use of GnRH agonists.
Male Contraception (goal, best option, methods)
Goal: Inhibit sperm production
Best option should include:
- Reversible
- Not Suppress libido
- Not suppress erectile function
Methods:
Condoms - 85% effective
Vasectomy - Reversibility?
Thermal male contraception - Hot tubs, underwear; effectiveness?
Drugs - Give testosterone & progestin to inhibit LH/FSH release to decrease sperm production; variability in population, only 60% of males become azospermic
Androgen Agonists :Testosterone, Methyltestosterone (MOA, PK, Pregnancy, Indications)
MOA: Acts as an agonist at the androgen receptor. Replaces the androgenic effects of testosterone including growth and maturation of prostate, seminal vesicles, penis and scrotum; development of male hair distribution, laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat disruption
PK: Multiple routes of administration available (buccal, intranasal, oral, SubQ, topical, sublingual, and transdermal)
Pregnancy: X
Indications: hypogonadism, testicular failure, anemia, stimulation of anabolic activity, gender dysphoria treatment, delayed puberty, male osteoporosis (off-label)
Androgen Agonists: Testosterone and Methyltestosterone (ADRs, Considerations)
ADRs:
Common—Acne, application site reaction, gynecomastia, enlarged prostate, headache, decreased LH release can result in gonadal atrophy, increase LDL, decrease HDL, premature closure of epiphyseal plates
Serious—Thromboembolic disorders (DVT, PE), benign prostatic hyperplasia, prostate cancer
BLACK BOX WARNING—Virilization has been reported in children who were secondarily exposed to testosterone gel or solution.
Considerations: Topical testosterone products are not interchangeable due to different strengths, doses, and application instructions. Not recommended for use in women or in men with breast or prostate cancer. Not recommend for use in patients with cardiac, renal or hepatic disease.
Formulations available for male contraception—testosterone enanthate + levonorgestrel, testosterone undecanate + medroxyprogesterone
acetate.
5 alpha-Reductase Inhibitors: Finasteride, Dutasteride; —asteride (MOA, PK, Pregnancy, Indications)
MOA: Inhibits 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT) in prostate, liver and skin. Finasteride is a selective inhibitor of type II 5α-reductase. Dutasteride inhibits both type I and type II 5α-reductase.
PK: Metabolized extensive via the CYP3A4 enzyme pathway; excreted 57% by fecal route and 39% by renal route
Pregnancy: X
Indications: Benign prostatic hyperplasia (BPH), androgenic alopecia, hirsutism (off-label), prostate cancer (off-label)
5 alpha-Reductase Inhibitors: Finasteride, Dutasteride; —asteride (ADRs and Considerations)
ADRs:
Common—Abnormal ejaculation, reduced libido, erectile dysfunction, gynecomastia, testicular pain, GI distress
Serious—Male breast cancer, prostate cancer
Considerations: Reduction in baseline PSA concentration by 50% within 6 months of therapy is indicative of efficacy. Improvement of benign prostatic hyperplasia (BHP) (eg. decrease in residual urinary volume and
increased urinary flow) indicates efficacy. Pregnant women should avoid exposure due to risk of HYPOSPADIAS in male fetus.
Androgen Receptor Antagonists: Flutamide, Bicalutamide, Nilutamide, Enzalutamide; —lutamide (MOA, PK, Pregnancy, Indications)
MOA: Competitively inhibits dihydrotestosterone (DHT) and testosterone binding to the androgen receptor
PK: Food does not impact absorption, dosed every 8 hours in prostate cancer
Pregnancy: D
Indications: Benign prostatic hyperplasia, metastatic prostate cancer, hirsutism in women
Androgen Receptor Antagonists: Flutamide, Bicalutamide, Nilutamide, Enzalutamide; —lutamide (ADRs and Considerations)
ADRs:
Common—Gynecomastia, impotence, decreased libido, decreased volume of ejaculate, hot flashes, diarrhea, nausea
Serious—Hepatotoxicity
BLACK BOX WARNING—Liver failure has been reported in patients. Hepatic injury occurs in first 3 months of therapy.
Considerations: Contraindicated in pregnancy and in patients with hepatic impairment. Androgen receptor antagonist treatment has the advantage of avoiding the initial flare of testosterone when continuous GnRH agonist monotherapy is used for prostate cancer.
Phosphodiesterase Type V (PDE5) Inhibitors: Sildenafil, Vardenafil, Tadalafil; —afil (MOA, PK, Pregnancy, Indications)
MOA: Increase cellular cGMP by blocking degradation of cGMP by PDE5, which results in smooth muscle relaxation. PDE5 is expressed mainly in corpus cavernosum, but also in retina and vascular smooth muscle cells.
PK: Taken 1 hour before sexual activity. For pulmonary arterial hypertension dosed every 4 to 6 hours.
Pregnancy: B
Indications: Erectile dysfunction, pulmonary arterial hypertension
Phosphodiesterase Type V (PDE5) Inhibitors: Sildenafil, Vardenafil, Tadalafil; —afil (Type Variants - PDE-5, PDE-6, PDE-11)
Sildenafil: Inhibits PDE-5, PDE-6, PDE-11
Vardenafil: Inhibits PDE-5, minimally effects on PDE-6, and no effect on PDE-11
Tadalafil: Inhibits PDE-5 and PDE-11, no effect on PDE-6,
PDE-5 localized in peripheral vascular tissue and tracheal smooth muscle (vasodilation and bronchodilation).
PDE-6 localized in rods and cones of eyes (blurry vision, blue/green vision).
PDE-11 localized in striated muscle (myalgias).
Phosphodiesterase Type V (PDE5) Inhibitors: Sildenafil, Vardenafil, Tadalafil; —afil (ADRs and Considerations)
ADRs:
Common—Flushing, dyspepsia, nausea, headache, angina and dizziness, changes in blue-green color vision
Serious—Myocardial infarction, nonarteritic ischemic optic neuropathy, sudden hearing loss
Considerations: Contraindicated to take with organic NITRATES which are NO donors and stimulate activity of guanylate cyclase because can cause life-threatening HYPOTENSION. Patients should report erection that persists longer than 4 hours.
