GnRH, secreted in a pulsatile manner by the hypothalamus, promotes LH and FSH release by the gonadatrophs of the anterior pituitary.

When GnRH is released at constant, high levels, LH and FSH release are inhibited!

Gonadorelin is a short acting GnRH analog.  Leuprolide is a long acting GnRH analog.  Therefore, leuprolide is used to maintain a constant high level of GnRH and inhibit Lh, FSH release.  This is useful in precocious puberty, breast and prostate cancer (hormone dependent), and endometriosis. 

On the other hand, because of gonadorelin's short half-life, it can be administered in a pulsatile manner, thereby stimulating LH and FSH release.  This is useful in conditions like hypothalamic hypogonadism, which would normally result in infertility.

Ganirelix and Cetrorelix are antagonists of GnRH that act on the gonadotroph GnRH receptors.

"Relix"

Recall that long-acting GnRH analogs such as leuprolide can also inhibit gonadotrophs when administered at a constant, high dose.  The difference between these two treatments is that leuprolide results in a transient/initial stimulation of LH, FSH release before becoming inhibitory.  Ganirelix/cetrorelix do not have this initial stimulation.

FSH stimulates gametogenesis.
In females, this means it stimulates follicular development. 

In males, it promotes spermatogenesis.

These are pharmacological agents containing FSH.  Menotropin (hMG) =FSH + LH

Follitropin = recombinant FSH

They are used in the treatment of infertility: ex from hypothalamic hypogonadism and polycystic ovarian syndrome. 

They are also used in IVF to stimulate follicle development before harvesting.

A long acting GnRH is administered to suppress the hypothalamic control of the pituitary and grant full control over LH and FSH release to the subsequent pharmacological inputs:

Menotropins are administered for 9-12 days to induce follicle development.  Then, a single dose of hCG (which mimics LH) is administered.  This mimics the LH surge and induces ovulation.

Diethylstilbestrol, like any estrogen replacement therapy, carries the risk of breast cancer and endometrial carcinoma in the women taking it.

In pregnant women on Diethylstilbestrol, the fetus is at increased risk for clear cell carcinoma of the vagina and cervix.

For this reason, DES is rarely used nowadays.

Estrogen causes the endometrium to grow during the menstrual cycle. 

Estrogen promotes female secondary sexual characteristics, and also influences the normal mineralization/osteoid formation... which is why a decrease in estrogen leads to osteoporosis risk.

hCG!  hCG acts like LH to stimulate Leydig cells into synthesizing testosterone.  The testosterone in the stroma of the testes (produced by the testes) is necessary for appropriate migration of the testes.

(Because the testosterone must be produced by the leydig cells in the stroma, just giving testosterone will not work)

finasteride blocks 5a-reductase to prevent the conversion of testosterone to dihydrotestosterone (DHT).

It is useful in benign prostatic hypertrophy, because the prostate responds strongly to DHT

Give drugs that inhibit the synthesis of gonadotropins and drugs that decrease the effect of the gonadotropins.  Therefore, give long-acting GnRH analogues at constant doses (goserelin, leuprolide) to block LH, FSH synthesis and therefore testosterone synthesis.

Give flutamide to block the effect of testosterone at its receptors (flutamide is an androgen-receptor blocker)

Recall that if you give just flutamide, the Testosterone levels would increase until they could competetively overcome the drug and the beneficial effect against the prostate cancer would be lost.

Also recall that these are used in adjunctive therapy... the other chemotherapeutic drugs are critical for the actual cancer therapy regimen (i.e. can't just give the hormonal drugs to treat cancer!)

Clomiphene is used to induce ovulation in women with PCOS.  It antagonizes estrogen receptors in the anterior pituitary and therefore blocks the negative feedback by estrogen on LH and FSH release.  LH and FSH increases, promoting ovulation.

PCOS patients produce higher levels of male hormones/androgens and too little LH/FSH to induce ovulation.

This is why they suffer from infertility (low FSH,LH) and acne/hirsuitism (high androgens)

Tamoxifen is an anti-estrogenic drug in breast tissue that is often added to breast cancer therapy.  Here, it is an estrogen receptor antagonist.

However, in the endometrium, tamoxifen has a pro-estrogenic effect, and therefore carries the risk of endometrial cancer with long term therapy.  For this reason, tamoxifen cannot be prescribed for any longer than 5 years.

Recall: this time limit is not necessary in patients with a hysterectomy!

Fulvestrant is an estrogen antagonist at both the breast and endometrium, and is only used in post-menopausal women

Raloxifene is an anti-estrogenic drug in both the breast and endometrial tissue! (used in postmenopausal women)  It also has a pro-estrogenic effect in bones, and can be prescribed for osteoporosis (but not first choice drug)

Mifepristone is a steroid progesterone antagonist that is used to induce abortion and to induce labor in cases of in utero fetal death.  It is used in combination with a prostaglandin (misoprostol).

As a progesterone antagonist, mifepristone will promote the detachment of the blastocyst from the implantation site.  (recall that progesterone is responsible for producing the proper endometrial environment for implantation.  At this point, PGE1 (misoprostol) is administered to cause uterine contraction and expel the products of conception.

(this procedure must be done within 49 days of conception)

Anastrazole is a competetive inhibitor of aromatase.  It is used as an adjunctive therapy in the treatment of estrogen-receptor-positive breast cancer.

(Letrozole is another competetive aromatase inhibitor)

Exemestane is an irreversible aromatase inhibitor

(as compared with Anastrazole, which is a competetive inhibitor)

"the aromatase is completely Ex'd"

What is Oxandrolone?

What are some side effects?

Oxandrolone is an androgen steroid with a much higher anabolic effect than androgenic effect.  It is used as a performance enhancer by athletes.

Because it decreases LH and FSH levels (negative feedback), oxandrolone causes infertility.  Because the leydig and sertoli cells are not stimulated by LH and FSH anymore, this leads to testicular atrophy.  Additionally, because LH no longer stimulates the leydig cells to produce testosterone, a decreased testosterone level results in feminization of men.  However, in women, the high androgen load from the steroid itself causes masculinization.

In children, it can lead to premature closure of the epiphyseal plates and stunted growth.

Finasteride inhibits 5a-Reductase, thereby inhibiting the synthesis of Dihydrotestosterone from Testosterone.

DHT acts on the prostate to stimulate growth, so finasteride is useful in BPH therapies.

(whereas flutamide is more useful in prostate cancer)

COCPs inhibit ovulation.  There is a direct negative feedback to the hypothalamus that blocks GnRh release, and therefore FSH and LH secretion.  There is no midcycle LH surge.

Progestin only pills do not always inhibit ovulation, but can prevent egg implantation by inhibiting the endometrial changes necessary to provide an appropriate implantation environment.

DVT (because leads to hypercoagulability of blood through increased clotting facter release)

Hypertension because of fluid and electrolyte retention

Hepatic Adenomas (normally regress with drug withdrawal)

Cancer (breast) with long term use

Cancer (cervical and endometrial) if giving estrogen only.  Combination with progestins actually causes a decreased risk!

Fetal malformations

Long acting GnRH analogues (leuprolide) and androgen receptor antagonists (flutamide) are combined to block the hormonal stimulation of prostate cancer.

(block both synthesis and effect of androgens)

Danazol is a synthetic androgen with progestational activity.  It is used to prevent attacks of hereditary angioedema and in cases of endometriosis.

It is helpful in endometriosis because it blocks ovarian release of estradiol.  It may also promote acne and hirsuitism by leading to increased androgen levels. 

Hereditary angioedema involves a defect in complement system inhibition.  This results in excessive activation of the kallikrein system, which promotes excessive bradykinin release.  Naturally, this leads to increased vascular permeability and edema of subcutaneous and submucosal tissues.  The high mortality rate is due to laryngeal edema causing asphyxiation.