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Infertility: Hormone Relationships: Preoptic Area and Hypothalamus GnRH (pulsatile) [note: continuous administration of GnRH has an inhibitory effect] Pituitary LH and FSH Ovaries and Testes estrogen, testosterone, inhibin (negative feedback on pituitary +/- hypothalamus except estrogen which can have + effect) Women: LH (E2) ovulation and steroidogenesis (estrogen) via mediation of cholesterol pregnenolone FSH oocyte and follicle recruitment for next ovulatory cycle Men: LH steroidogenesis (testosterone) via mediation of cholesterol pregnenolone FSH germ cell maturation (spermatogenesis) Hypogonadism: Tertiary: Hypothalamic problem: low LH and FSH Secondary: Pituitary problem: low LH and FSH Primary: Gonad problem: low estrogen/testosterone with high LH and FSH Consider a pulsatile GnRH stimulation test to evaluate secondary/tertiary vs. primary hypogonadism Menopause: Drop in estradiol loss of negative feedback on pituitary increase in LH and FSH (seen in urine) Infertility Problems: R/O other causes of infertility (i.e. thyroid dysfunction, hyperprolactinemia, polycystic ovarian syndrome) Ovulation Induction (OI): for pts NOT ovulating (PCOS, hypogonadotropic hypogonadism, hyperprolactinemia) - cases where gonads are FINE Goal: create a dominant follicle Controlled Ovarian Stimulation (COS): for pts already ovulating, but structural abnormalities, etc, make pregnancy less likely Goal: create MULTIPLE follicles Hyperprolactinemia: inhibition of GnRH release caused by prolactin TRH anterior pituitary prolactin (inhibited by dopamine/PIF) S/S: primary amenorrhea, galactorrhea, female infertility Etiology: pituitary cancer, medications Drug Name MOA GnRH Agonist Continuous administration Continuous application of exogenous GnRH inhibits gonadotropin (LH) release GnRH Agonist Continuous Administration Drug Class Indications AE/DI/CI "Long" IVF protocol 7-10 days to suppress gonadotropin release Precocious puberty CI: Pregnancy (Category X) Lactation Other Anemia Endometriosis SQ or intranasally throughout follicular phase GnRH Antagonist Cetrorelix (Cetrotide) Ganirelix (Antagon) GnRH Antagonist Pharmacokinetics/ dynamics Long latency Inhibits endogenous GnRH release, preventing premature LH surge during ovarian hyperstimulation Short latency Rapid onset SQ during mid-late follicular phase Prostate Cancer Breast Cancer "Short" IVF protocol AE: Anaphylaxis (Cetrorelix) - rare CI: Pregnancy (Category X) Up to 16% lower pregnancy rate compared to GnRH AGONISTS Drug Class Drug Name MOA Pharmacokinet/ dynam Indications AE/DI/CI Other Follitropin (FSH) Stimulates follicular growth, maturation, and gonadal steroid production r-FSH has a shorter half-life than u-FSH Oocyte recruitment AE: Ovarian Hyperstimulation Syndrome (OHSS) (less than with hMG) OHSS: Bloating Fullness Nausea Diarrhea Wt Gain Vomiting Darker/No Urine SOB Pleural Effusion Calf Pain Chest Pain Urofollitropin (u-FSH) u-FSH: purified from Bravella postmenopausal urinary Fertinex (purified) FSH _________________ Gonadotropins Recombinant Follitropin (r-FSH) $$$ Cannot be used alone in women with hypogonadotropic hypogonadism b/c of the low LH levels CI: Pregnancy (Category X) r-FSH: synthetically created Follitropin alfa (Gonal-F RFF) Follitropin beta (Follistim AQ) Human Menopausal Gonadotropins (hMG) Gonadotropins IM SQ In vitro fertilization Combination FSH and LH (menotropins) Menopur (SQ) Repronex (SQ or IM) Pergonal Stimulates follicular growth, maturation, and gonadal steroid production Ovulation induction IM once after follicle maturation Derived from urine of postmenopausal women Infertility hypogonadotropic hypogonadism Men and women IM 3x / wk In vitro fertilization AE: Ovarian Hyperstimulation Syndrome (OHSS) Multiple Pregnancy CI: Pregnancy (Category X) Drug Class Drug Name MOA Human Chorionic Gonadotropin (hCG) Released from the syncytiotrophoblasts of the placenta to maintain the corpus luteum's production of progesterone which prevents contractility of the uterus u-hCG Pregnyl Profasi Chorex Novarel Gonadotropins Recombinant human chorionic gonadotropin (r-hCG) Choriogonadotropin alfa (Ovidrel) hCG mimics the physiologic LH surge LH receptor agonist u-hCG: purified from urine of pregnant women Pharmacokinet/ dynam Indications Hypogonadotropic hypogonadism in men (supports testosterone production, which impacts Sertoli cells, but does NOT directly impact initiation of spermatogenesis) Ovulation induction following ovarian follicle maturation AE/DI/CI Other Mimicking of LH causes testosterone production in male fetuses when hCG levels increase Drug Name MOA Pharmacokinet/ dynam Indications AE/DI/CI Other SERMs Selective Estrogen Receptor Modulator Induces ovulation: T1/2 = 5-7 days Increases GnRH, FSH, LH PO x 5 days secretion Ovulation Induction in pts with Adequate HPO function and PCOS Lower cost than gonadotropins Clomiphene Partial agonist nature of SERM prevents estrogen's negative feedback on hypothalamus Infertility: Ovulatory disorder PCOS Idiopathic AE: Hot flushes (10-20%) Ophthalmic: Blurring Spots Flashes (most reversible) Ovarian Enlargement Multiple Pregnancy Ovulation Induction Agents Ovulation Induction Agents Drug Class CI: Pregnancy Category X SERMs Selective Estrogen Receptor Modulator Mixed estrogen receptor agonist/ antagonist Uterine and bone agonist Ovulation Induction in pts with Adequate HPO function and PCOS Tamoxifen Breast and hypothal antagonist FDA approved for various breast CAs Similar effectiveness to clomiphene Precaution with existing ovarian hypertrophy AE: Flushing (40-80%) Pregnancy Category D Ovulation Induction Agents Drug Class Drug Name MOA Pharmacokinet/ dynam Indications AE/DI/CI Aromatase Inhibitors Decreases estrogen production PO x 5 days AE: Hot flushes Nausea Anastrozole (Arimidex) Decreases negative feedback Ovulation Induction in pts with Adequate HPO function and PCOS Ietrozole (Femara) Increases GnRH, FSH, and LH May also modestly increase androgen levels increased follicular sensitivity to FSH Ovulation Induction Agents Ovulation Induction Agents Metformin Decreases hepatic glucose production FDA approved for Breast CA Alternate to clomiphene Used after clomiphene failure/intolerance Similar effectiveness to clomiphene Ovulation Induction in pts with Adequate HPO function and PCOS FDA approved for Type 2 DM Gonadotropins SEE ABOVE Other Increases menstrual cyclicity Improves spontaneous ovulation Ovulation Induction in pts with Adequate HPO function and PCOS Does NOT improve birth rates Ovulation Induction Agents Drug Class Drug Name MOA Pharmacokinet/ dynam Non-selective dopamine receptor agonist T1/2 = 6-20 hr Ovulation Induction in pts with PO Bromocriptine (Parlodel) Hyperprolactinemia Induced Infertility Ovulation Induction Agents Ovulation Induction Agents AE/DI/CI Ovulation Induction in pts with Secondary hypogonadism Gonadotropins + hCG Dopamine Agonists Indications In vitro fertilization protocol AE: Lightheadedness HA Dizziness Nervousness Fatigue Nausea Abd Pain Diarrhea No longer used for postpartum breast engorgement in nonbreastfeeding mothers Dopamine Agonists Cabergoline (Dostinex) Long-acting selective D2 receptor agonist T1/2 = 65 hrs Dosed 2x / wk Inhibits release of prolactin PO Ovulation Induction in pts with Hyperprolactinemia No longer used for postpartum breast engorgement in nonbreastfeeding mothers AE: Lightheadedness HA Dizziness Nervousness Fatigue Nausea Abd Pain Diarrhea Other Controlled Ovarian Stimulation Agents Controlled Ovarian Stimulation Agents Drug Class Drug Name Pharmacokinet/ dynam Indications Non-ART (assisted reproduct. technology) Regimens: Oral OI (see above) + Gonadotropins +/hCG ART: In vitro fertilization Stage 1: COS with: GnRH analog, FSH (gonadotropins), +/OC Stage 2: OI with hCG ART: Controlled Ovarian Stimulation Agents MOA Controlled Ovarian Hyperstimulation Stage 3: Luteal phase support with progesterone Follicle development: gonadotropin injections Oocyte maturation: hCG injection Luteal phase and prevention of premature LH surge: progesterone + GnRH agonist/ antagonist Preparation for ART (in vitro fertilization) AE/DI/CI Other Vitamin Supplementation Gonadotropins Gonadotropins Drug Class Drug Name MOA Pharmacokinet/ dynam Indications Conventional Protocol: SEE ABOVE hCG 8-12 weeks Male Infertility hMG remaining time of 4-6 mo regimen hCG followed by hMG Alternative Protocols: Clomiphene may increase sperm concentrations Male Infertility Urofollitropin r-FSH Clomiphene Antioxidant Vitamin Supplementation: Zinc Magnesium Vitamin E L-carnitine Male Infertility AE/DI/CI Other