Ovarian hyperstimulation

De, L. A., MontaneUi, L., Van, D. J., et al. (2006) Presence and absence of foUicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J. Clin. Endocrinol. Metab. 91, 555-562. 

Gonadotropins are used to treat infertility in women with potentially functional ovaries who have not responded to other treatments. The therapy is designed to simulate the normal menstrual cycle as far as is practical. A common protocol is daily injections of menotropins for 9 to 12 days, until estradiol levels are equal to that in a normal woman, followed by a single dose of hCG to induce ovulation. Two problems with this treatment are risks of ovarian hyperstimulation and of multiple births. Ovarian hyperstimulation is characterized by sudden ovarian enlargement associated with an increase in vascular permeability and rapid accumulation of fluid in peritoneal, pleural, and pericardial cavities. To prevent such occurrences, ovarian development is monitored during treatment by ultrasound techniques and by measurements of serum levels of estradiol. 

Recommended dosage and monitoring requirements According to Micromedex, the usual starting dose of Follistim is 150 to 225 lU per day injected intramuscularly or subcutaneously, adjusted accordingly on an individual basis. The initial dose of 75 lU per day for 7 to 14 days is employed in anovulatory women who have not responded to clomiphene citrate treatment. The initial dose of 150 lU per day, followed by a maintenance dose of 75 to 375 lU per day for 6 to 12 days, is employed for controlled ovarian hyperstimulation followed by assisted reproduction. 

G. Other applications Limited data show some beneficial effects of leuprolide in the treatment of breast cancer. According to Micromedex, there is good documentation that leuprolide is effective for bowel pain and nausea associated with irritable bowel syndrome. Leuprolide has been used for controlled ovarian hyperstimulation to enhance the in vitro fertilization-embryo transfer procedure. In endometriosis, the goal of treatment is pain relief and reduction of endometriotic lesions. In children with central precocious puberty, stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females, respectively. 

Indications Inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation... 

Inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation NA Af-acetyl-3-(2- naphthyl)-D- alanyl-4-chloro-D- phenylalanyl-3-(3- pyridyl)-D-alanyl-L- seryl-L-tyrosyl-9 N 9, AflO-diethyl-D- NA... 

In women treated with gonadotropins and hCG, the two most serious complications are the ovarian hyperstimulation syndrome and multiple pregnancies. Overstimulation of the ovary during ovulation induction often leads to... 

SUPPRESSION OF GONADOTROPIN PRODUCTION Controlled Ovarian Hyperstimulation... 

Four synthetic decapeptides that function as competitive antagonists of GnRH receptors are available for clinical use. Ganirelix, cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose-dependent manner. Ganirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures, whereas abarelix and degarelix are approved for men with advanced prostate cancer. 

When used for controlled ovarian hyperstimulation, ganirelix and cetrorelix are well tolerated. The most common adverse... 

Follitropin alfa Activates FSH receptors Mimics effects of endogenous FSH Controlled ovulation hyperstimulation in women infertility due to hypogonadism in men SC injection 3-7 x/wk Toxicity Ovarian hyperstimulation syndrome and multiple pregnancies in women gynecomastia in men headache, depression, edema in both sexes... 

Leuprolide Agonist of GnRH receptors Increased LH and FSH secretion with intermittent administration reduced LH and FSH secretion with prolonged continuous administration Ovarian suppression, controlled ovarian hyperstimulation, central precocious puberty advanced prostate cancer Administered IV, SC, IM or intranasally depot formulations are available Toxicity Headache, lightheadedness, nausea, injection site reactions t symptoms of hypogonadism with continuous treatment... 

Lubi prostone (Amiriza) [Laxative] Uses Chronic idiopathic constipation in adults Action Selective Cl channel activator Dose Adults. 24 meg PO bid w/ food Contra Mechanical GI obst Caution [C, /—] Severe D, severe renal or mod-severe hepatic impair Disp Gel, caps meg SE N, HA, D, GI distention, abcl pain EMS Monitor for signs of electrolyte disturbances and hypovolemia d/t D OD May cause severe D, hypovolemia, and abd pain/cramps give IV fluids Lutropin Alfa (Luveris) [Hormone] Uses Infertility Action Recombinant LH Dose 75 Units SQ w/ 75-150 Units FSH, 2 separate inj max 14 cl Caution [X, /M] Contra Primary ovarian failure, uncontrolled thyroicl/adrenal clysfxn, intracranial lesion, AUB, hormone-dependent GU tumor, ovarian cyst, PRG Disp Inj SE HA, N, ovarian hyperstimulation synd, breast pain, ovarian cysts T risk of multiple births EMS None OD Unlikely to cause life-threatening Sxs... 

In 71 women undergoing in vitro fertilization and embryo transfer using recombinant human follicle-stimulating hormone in doses sufficient to attain a pregnancy rate of 24% (10), the main adverse effect was mild pain at the site of injection (less than 20% of patients) but there were two cases of ovarian hyperstimulation syndrome. In less than 10% of patients, redness, swelling, or bruising was seen and one patient developed headache. 

When recombinant and urinary versions of follicle-stimulating hormone were compared under double-blind conditions in an in vitro fertilization program in a randomized, multicenter study (12), the former was more potent. There were no clinically relevant differences in safety between the two products and no cases of ovarian hyperstimulation syndrome. 

More exact data on the adverse effects and relative safety of the recombinant and urinary formulations have been provided in a similar investigation in 259 women (15). In terms of safety, rhCG was well tolerated at a dose of up to 30 000 IU. Moderate ovarian hyperstimulation syndrome was reported in 12% of patients who received uhCG and 12% of those who received two injections of rhCG. There were no moderate or severe... 

There is a risk of ovarian hyperstimulation when an ovulation-inducing drug is followed by rapid ovarian enlargement with peritoneal effusion. The incidence of these complications varies with the product and dosage schedule used in experienced hands, the frequency of complications may be no more than about 4%. 

While it is possible that the gonadotropins themselves induced SIADH, it seems more likely that it was a secondary complication of ovarian hyperstimulation. 

A 33-year-old woman developed severe symptomatic ovarian hyperstimulation after being given 10 000 IU of urinary human chorionic gonadotropin for empty follicle syndrome (22). 

Other presenting signs of ovarian hyperstimulation include ascites, hydrothorax, thrombophlebitis, and, as in one recently reported case, acute dyspnea (24). 

In a study of the relevance of the serum concentration of human chorionic gonadotrophin in 849 IVF cycles there were no significant relations between hCG concentrations and the proportion of follicles yielding oocytes, the fertilization rate, blastulation rate, or the probabilities of embryo transfer, implantation, or clinical pregnancy (32). This result again stresses the desirability of using moderate doses of hCG, which seems to reduce the risk of ovarian hyperstimulation while maintaining efficacy. 

Urine-derived urofollitropin and recombinant FSH appear to be equally effective and well tolerated for induction of ovulation (34). However, it is unclear whether human menopausal gonadotropins have a higher risk of overstimulation and ovarian hyperstimulation syndrome than urofollitropin in women with polycystic ovary syndrome. 

A generalized allergic reaction to human menopausal gonadotropin (Pergonal) has been described during controlled ovarian hyperstimulation (40). In this case a desensitization protocol allowed the patient to complete her treatment cycle without further problems. Subsequently recombinant follicle stimulating hormone was used successfully and uneventfully. 

The incidence of ovarian hyperstimulation is highly dependent on the therapeutic regimen. In one study (65) the following methods were compared ... 

---