FEMALE GONADAL PHARMACOLOGY:

Estrogens:
- Structure: 18-carbon backbone and contain a phenolic A ring (required for high affinity binding to estrogen
receptor)
- Naturally Occurring Estrogens:
o 17-B Estradiol (E2): most potent, most abundant
o Estrone (E1): 10x less biologically active than estradiol
o Estriol (E3): synthesized by the placenta (present in high concentrations during pregnancy)
- Synthesis of Estrogens: steroid hormone with cholesterol backbone
o Premenopausal Women: ovarian aromatase converts androstenedione to estrogen (in follicular
cells)
o Postmenopausal Women: adrenal DHEA converted to estrogen by aromatase in adipocytes
o Men: aromatase converts androstenedione to estrogens in adipose tissue; testes produce a small
amount
o Pregnancy: placenta produces a large amount of estriol
- Pharmacology of Estradiol:
o Tissue Distribtution: lipophilic and distributes rapidly to tissues
o Bioavailability: readily absorbed in via the GI tract, skin and mucus membranes
o Rapid Hepatic Metabolism: short half life when taken orally due to first pass effect
Hepatic metabolites renally eliminated or may undergo enterohepatic recirculation
Micronized estradiol allows for better bioavailability
- Estrogen Derivatives (Synthetic):
o Agents:
Ethinyl estrogen
Mestranol (demethylated in the liver to ethinyl estrogen)
o Pharmacokinetics:
Bypass First Pass Effect: C17 modification inhibits first pass effect
Circulation: not bound to SHBG (free in circulation)
Release: slowly released from adipose tissue
- Adverse Effects of Estrogen:
o Postmenopausal bleeding (minimize dose, co-administer progestin)
o Nausea
o Breast tenderness
o Hyperpigmentation
o Migraine headaches
o Cholestasis
o Hypertension
- Estrogen Risks:
o Endometrial cancer
o Breast cancer
o CV outcomes (possible increased risk for primary CHD events, stroke/TIA, DVT)
- Estrogen Benefits:
o Decrease risk of hip or other fracture
o Decrease risk of colorectal cancer
- Estrogen Contraindications:
o Estrogen dependent neoplasm
o Undiagnosed genital bleeding (must first determine cause)
o Hepatic disease (risk for cholestasis)
o History of thromboembolic disorder (increased risk fo clots)
o Pregnancy (category X)
Progestins:
- Synthesis of Progesterone:
o Synthesized/secreted from corpus luteum during luteal phase of menstrual cycle (in response to LH
surge)
o If pregnancy/implantation occurs:
Initially, trophoblast secretes hCG to sustain corpus luteum and progesterone levels
After 8 weeks, placenta secretes estrogen and progesterone (no longer requires corpus luteum)
- Synthetic Progestin:
o Northeindrone
o Medroxyprotesterone
- Progestin Pharmacology:
o Development of secretory endometrium during secretory phase of menstrual cycle
o Secretion just prior to ovulation leads to 1 degree rise in body temperature
o Maintenance of pregnancy (suppresses menstruation and uterine contractility)
o Proliferation of mammary gland acini during pregnancy
- Pharmacokinetics:
o Rapidly absorbed orally
o Large first pass effect (similar to estrogen)
o Synthetic derivatives and micronized progesterone allow for better oral bioavailability
 Therapeutic Uses of Estrogen and Progesterone:
- Hormone replacement therapy
- Primary hypogonadism (stimulate secondary sex characteristics)
- Dysmenorrhea
- Endometriosis
- Endometrial cancer
- Prostate cancer
- Contraception
- PCOS
Hormone Replacement Therapy:
- Basics:
o Estrogen used alone if NO uterus present (ie. hysterectomy)
o Estrogen + progesterone if uterus present (due to increased risk for endometrial hyperplasia)
- Use:
o Relieve moderate to severe menopausal symptoms (hot flashes, sweating, atrophic vaginitis, sexual
dysfunction)
o Reduce bone resorption/osteoporosis prevention (only used for osteoporosis if also treating
menopausal symtpoms)
Does NOT restore bone loss (only preventative)
May be considered in patients with high risk of osteoporosis (smokers, thin, Caucasian,
sedentary, family Hx)
- Drug Interactions:
o Drugs Interfering with HRT: decreased efficacy of HRT
Rifampin
Anticonvulsants
Some antibiotics
o HRT Interferes with Efficacy of Other Drugs: decreased efficacy of other drugs
Warfarine
Benzodiazepines
Thyroid agents
Metformin
Polycystic Ovary Syndrome:
- Basics: treatment revolves around symptoms and patient goals
o Reduce androgenic symptoms
o Weight loss (for obese patients)
o Reduction of insulin levels
o Address fertility goals
- Goal of Therapy: early diagnosis and treatment may reverse some of the risks associated with PCOS
- Lifestyle Modification:
o Weight Loss
Regular aerobic exercise
Controlled eating patterns (carbohydrate, fat and calorie reduction)
Pharmacologic agents (ie. Orlistat)
o Avoid Tobacco
- Therapy for Androgen Excess:
o Hair Removal (Hirsutism):
Mechanical hair removal
Eflornithine cream (inhibits ornithine decarboxylase to RETARD hair growth)
o Oral Contraceptives: estrogen and progestin combination therapy
Estrogen:
Decreases LH decreased androgen production
Increases SHBG less free androgens
Progestin: need to use derivatives with the LEAST androgenic effects (norgestimate,
desogestrel, drospirenone)
Benefits of OCP Use:
Improve hirsutism and acne
Protection against unopposed estrogen in the endometrium
Induces withdrawal bleed
Concerns Regarding OCP Use:
Insulin resistance
Glucose intolerance
Vascular reactivity and coagulability
o Spironolactone:
MOA: inhibits androgen biosynthesis AND competitive inhibitor of the androgen receptor (large
doses)
 Use: synergistic effects with oral contraceptives
Use if hirsutism or acne uncontrolled despite OCP therapy
Adverse Effects:
Vaginal bleeding
Hyperkalemia (K sparing diuretic)
o Other Agents:
Flutamide: androgen receptor antagonist (limited use in PCOS)
Glucocorticoids: HPA axis suppression to decrease ACTH and androgen production (limited
use due to SEs)
Finasteride: inhibition of type 2 5-reductase enzyme (limited use in PCOS)
- Endometrial Protection:
o Why is it required?
Patients with PCOS suffer from CHRONIC ANOVULATION
Increases risk for endometrial hyperplasia
Increases risk of dysfunctional uterine bleeding
Possible increase risk for endometrial cancer
o Combined OCPs:
Progestin antagonizes endometrial proliferation (estrogen effect)
Requires a documented NEGATIVE pregnancy test before starting on OCP
If patient does not have menstrual period for >6 weeks:
Give medroxyprogesterone daily for 10 days to induce withdrawal bleeding
Minimizes breakthrough bleeding when starting OCP
o Medroxyprogesterone Acetate:
Used when OCPs are contraindicated or patient does not want to go on them
Given every day for 7-10 days every 1-2 months
Induces withdrawal bleed, offering endometrial protection
Does NOT reduce acne or hirsutism
Does NOT provide contraception
o Metformin:
Restores menstrual cyclicity
Protective effects on endometrium not well established
- Therapy for Induction of Ovulation:
o Weight Loss: decreases serum testosterone, allowing for reduction of ovulation and pregnancy
o Metformin: alone or in combo with clomiphene
o Clomiphene: increases FSH and LH; 80% of PCOS women ovulate in response
o Thiazolidinediones: rosiglitazone +/- clomiphene
o Gonadotropin therapy
- Therapy for Insulin Resistance:
o Weight Loss: reduces insulin levels
o Metformin: MAINSTAY OF THERAPY*
MOA: improves hepatic insulin sensitivity
Decrease hepatic glucose output
Decrease circulating insulin
Decreased androgen production in the theca cells
Additional Benefits:
Weight loss
Decreased BP and LDL
Improved ovulation
Decreased rates of spontaneous miscarriage
Decreased gestational diabetes
o Thiazolidinediones:
Agents: rosiglitazone, pioglitazone
MOA: improves insulin sensitivity in adipose tissue, skeletal muscle and liver
Improved glucose uptake
Decreased circulating insulin
Decreased androgen production in theca cells
- AACE PCOS Recommendations:
o Early recognition of the syndrome
o Lifestyle modification
o Measurement of glucose +/- insulin (consider OGTT)
o Detect and treat lipid abnormalities
o Monitor and treat BP if necessary
o Measure atherogenic markers
o Initial treatment with metformin (especially if overweight/obese)
o Nonandrogenic OCPs for androgenic symptoms
o TZDs for impaired glucose tolerance (IGT) or T2DM
Fertility Pharmacology:
- Goals:
 o Ovulation induction (to induce an anovulatory female to ovulate 1 follicle)
o Superovulation (to induce multiple ova to mature and ovulate in a normally ovulating female, the
chance of pregnancy)
- Clomiphene Citrate:
o MOA: competitive antagonist of the estrogen receptors in the hypothalamus
Hypothalamus detects hypoestrogen state and increase GnRH release
Pituitary stimulated to release 50-60% more FSH (results in follicular development)
Only effective in women with adequate estrogen levels
o Administration:
Administered for 5 days early in the follicular phase (days 3-7 or 5-9)
Administered at this time because it is before the follicle dominance occurs, increasing the
change of multiple follicle recruitment and maturation (increased FSH increased follicles)
o Adverse Effects:
Antiestrogen effects (hot flashes, inhibition of endometrial proliferation)
Risk for multiple gestation
Ovarian cancer (controversial association)
- Aromatase Inhibitors:
o MOA: block conversion of androgen to estrogen
Decreases estrogen negative feedback to hypothalamus, increasing GnRH and FSH
o Features:
Similar dosing regimen to clomiphene
No anti-estrogenic effect at the endometrium
More commonly used for estrogen-sensitivty malignancies
- Gonadotropins:
o Basics: injectable FSH and LH
o FSH: administered once daily subQ for duration of follicular phase
May inhibit normal LH surge, resulting in need to exogenously produce LH surge
Derived from purified menopausal urine OR recombinant FSH
o Mimic LH Surge with Injectable HCG:
Has a longer half life than exogenous LH
Stimulates ovulation and final maturation of ova (becomes fertilzable)
Ovulation typically occurs 34-36 hours after hCG administration
Derived from pregnant womens urine OR recombinant hCG
o Effects: 8-15% chance of conception with each cycle
20%, 5% triplets, risk for quadruplets or more
o Monitoring:
Trans vaginal ultrasound (assess number of mature follicles)
If too many, stop FSH and do NOT give hCG (cancel cycle)
Serum estradiol
o Complications:
Ovarian Hyperstimulation Syndrome (OHSS):
Seen in women given ovulation induction or superovulatory drugs
Excess vasoactive substances released during follicle leutinization (esp. VEGF)
o Increases capillary permeability (ascites, hypovolemia, hemooncentration)
Occurs 5-10 days after ovulation trigger

MALE GONADAL PHARMACOLOGY:

Uses of Androgens:
- Hypogonadism
- Male sexual dysfunction
- Catabolic states
- Athletic performance
- Erythropoiesis stimulation
Androgen Formulations:
- 17-Hydroxyl Group Esters:
o Esterification makes the more lipophilic (oil preparations)
o Hydrolyzed to testosterone in circulation
o Administered IM every 1-2 weeks
o Adverse Effects:
Cough (unclear mechanism)
Pain at injection site
Fluctuations in serum testosterone and symptoms
- 17-Alkylated Testosterone (Methyltestosterone):
o Alkyl group retards hepatic metabolism, allowing for oral use
o Less androgenic than testosterone
o Associated with liver toxicity (not recommended for use)
o Also difficult to monitor therapy (not easily detectable via immunoassay)
- Transdermal Delivery:
 o Patch: applied to back, abdomen, upper arms or thighs
2.5 or 5mg patches
Some adverse site reactions (rotate site or use hydrocortisone cream)
o Gel: administer 5 gm of gel once daily
Allow gel to dry and cover with clothing
Do not come into contact with women/children
Better skin tolerability than patch
- Buccal Testosterone (Striant):
o Small tablet that adheres to the gums (becomes moistened and molds to it)
o Testosterone absorbed through the gums into the bloodstream (bypasses liver metabolism)
o Adverse effects include taste changes
- Testosterone Pellets:
o 3-6 pellets implanted subcutaneously (lasts up to 6 months)
o Pellets may extrude spontaneously
Monitoring Testosterone Therapy:
- Serum Testosterone Levels:
o Goal: 3-6 months after the initiation of therapy, testosterone should be in the middle of the normal
range
o Checking Serum Testosterone Levels:
Injectable: check midway between injections
Patch: check 3-12 hours after application
Buccal: check immediately before or after application
Gels: check anytime after the first week of therapy
Pellets: check at the end of the dosing interval (adjust the number of pellets/next dosing
interval accordingly)
- Hematocrit:
o Check:
Baseline level
Levels at 3-6 months
Levels annually after that
o Importance: discontinue if hematocrit >54% (reintroduce at a lower dose when it normalizes)
- Bone Mineral Density: check after 1-2 years OR if osteoporosis or fracture occurs
- Prostate Screening:
o Baseline: PSA/DRE (for men >40 years old with PSA >0.6ng/ml)
o Follow Up: at 3-6 months after initiating therapy, and then per cancer screening guidelines after that
- Symptom Improvement: in 3-6 months and then annually
o Sign/Symptom Improvement:
Increased libido
Improved erectile dysfunction
Improved fertility
Improved weakness, fatigue
Improved depression, loss of motivation, irritability
Increased body hair
Increased muscle ass
Increased size of prostate/testes
Reduction in gynecomastia
Improvement of osteoporosis
Improvement of anemia
- Adverse Drug Reactions: in 3-6 months and then annually
Contraindications to Testosterone Therapy:
- Metastatic prostate cancer
- Breast cancer
- Unevaluated prostate nodule or induration
- Elevated PSA >4ng/ml (or 3ng/ml is high risk- AA, first degree relative)
- Hct >50%
- Severe lower urinary tract symptoms with BPH
- Uncontrolled CHF
Adverse Effects of Testosterone Therapy:
- Erythrocytosis (esp. if predisposed- COPD, chronic hypoxia)
- Acne/oily skin (androgenic stimulation of sebaceous glands)
- Detection of subclinical prostate cancer
- Reduced sperm production/fertility (feedback inhibition of LH/FSH)
- Induction/worsening of obstructive sleep apnea
- Virilization in women and children (facial hair, hirsutism)
- Initial growth spurt in children without epiphyseal closure, followed by premature closure and stunted growth
- Aromatization of androgens to estrogen (gynecomastia)
Anabolic Steroids:
- Oxandrolone, Stanozol:
o Only oxandrolone available in the US
 HIV/AIDs wasting
Post-burn patients who have lost muscle mass
o Greatest ratio of protein anabolic effects (ie. increase muscle mass) compared to virilizing effects
- Androstenedione:
o Weak natural androgen (synthesized by adrenal glands)
o Converted to testosterone in tissues by 17-dehydrogenase
o May aromatize to estrogen
- Tetrahyrogestrinone (THG):
o Newer anabolic that is metabolized quickly and more difficult to detect
o ~20% of the potency to DHT
o Toxicity profile is unknown
- Danazol:
o Derivative of 17-ethinyl testosterone
o Weak progestin and androgen activity
o Used in the treatment of endometriosis (suppresses ovarian function- inhibits midcycle LH surge and
FSH)
- Side Effects of Anabolic Steroids:
o No serious side effects with short term use
o Long term use associated with several side effects
CV risk factors (decreased HDL, increased TG)
Hepatotoxicity (with oral anabolics)
Behavioral effects (increased aggressiveness, irritability)
Infertility
Anti-Androgens:
- Uses of Antiandrogens:
o Female virilization
o Alopecia
o Precocious puberty
o Prostate cancer
o BPH
o Paraphilia
- GnRH Receptor Agonists:
o Agents:
Leuprolide
Goserelin
Triptorelin (long acting, considered for use in paraphilia)
o MOA: continuous stimulation of GnRH receptor causes downregulation
Because of mechanism, initially results in surge of testosterone
- GnRH Receptor Antagonists:
o Centrorelix: IVF protocols, inhibit premature LH surge (allows doctors to retrieve eggs before
ovulation)
o Ganirelix: IVF protocols, inhibit premature LH surge
o Degarelix: prostate cancer
o Abarelix: palliative care in prostate cancer (not available in the US)
- Non Steroidal Androgen Receptor Antagonists:
o Flutamide: used in prostate cancer
High incidence of hepatotoxicity
Associated with gynecomastia
Requires dosing every 8 hours
o Bicalutamide: used in prostate cancer
Lower incidence of hepatotoxicity
Dosed once daily
- 5-Reductase Inhibitors:
o Agents:
Finasteride
Dutasteride
o MOA: block conversion of testosterone to DHT
o Indications:
BPH (both agents)
Androgenic alopecia/male pattern baldness (finasteride only)
o Adverse Effects:
Induces genital abnormalities in male fetus (avoid in pregnancy)
Decreased libido and sexual dysfunction
- Other Antiandrogen Agents:
o Ketoconazole:
Antifungal agent that inhibits glucocorticoids and androgen synthesis in the adrenal gland
o Spironolactone:
Competitive androgen receptor angtagonist and K sparing diuretic
 Used to treat hirsutism and PCOS