Gonadotropins

General adverse effects and adverse reactions

The short- and long-term effects of ovulation induction have been reported [ ]. In the short term, clomiphene and gonadotropins cause ovarian hyperstimulation syndrome (ovarian enlargement, bloating, and nausea) and multiple pregnancies; gonadotropins also cause ectopic pregnancy. In the long term, clomiphene may cause an increased risk of ovarian cancer.

Recombinant human chorionic gonadotropin

Recombinant human luteinizing hormone has now very largely replaced the product prepared from the urine of pregnant women (uhCG). In an open, randomized trial in 297 ovulatory infertile women in 20 US infertility centers, recombinant hCG 250 micrograms and 500 micrograms was compared with urinary hCG 10 000 U USP in assisted reproduction [ ]. The women were treated for a single cycle with one or the other. The mean numbers of oocytes retrieved per treatment group were equivalent [ , ]. Although the numbers of fertilized oocytes on day 1 after oocyte retrieval and of cleaved embryos on the day of embryo transfer were significantly higher with 500 micrograms of recombinant hCG than with 250 micrograms, the incidence of the anticipated adverse events also tended to be higher.

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 [ ]. 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 complications in patients who received a single dose of rhCG up to 30 000 IU. The results seem to show that a single dose of rhCG is effective in inducing final follicular maturation and early luteinization in in vitro fertilization and embryo transfer patients and is comparable with uhCG 5000 IU. The dose of rhCG that gave the highest efficacy to safety ratio was 15 000–30 000 IU.

The recombinant and urinary forms of human chorionic gonadotropin have also been compared in an international multicenter study, with similar findings [ ], but it was notable that significantly more patients who were given uhCG reported local reactions (particularly inflammation and pain), presumably because of the presence of biological impurities.

Observational studies

The European Metrodin HP Study Group has assessed the efficacy and safety of a highly purified urinary FSH in combination with human chorionic gonadotropin in inducing spermatogenesis in 28 men with primary complete isolated hypogonadotrophic hypogonadism, of whom 25 achieved spermatogenesis [ ]. Mean testicular volume increased by about 7 ml during treatment. Adverse events considered to be related to human chorionic gonadotropin were acne (n = 3), weight gain (n = 2), and gynecomastia (n = 1). Acne can be attributed to increased testosterone. Gynecomastia is an adverse effect of human chorionic gonadotropin treatment [ ], and it may be caused by raised serum estradiol concentrations.

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% [ ], 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.

The efficacy of recombinant human luteinizing hormone (rhLH) for supporting follicular development induced by recombinant human follicle-stimulating hormone (rhFSH) has been investigated in hypogonadotropic hypogonadal women [ ]. A total of 42 adverse events were reported in 14 of the 53 cycles in this study. Of these, 32 adverse events occurred in 11 of the 42 cycles treated with rhLH, and 10 occurred in three of the 11 cycles not treated with rhLH. The most frequent adverse events were pelvic and abdominal pain, headache, breast pain, nausea, ovarian enlargement, and somnolence. These adverse events are similar to those reported during therapy with follicle-stimulating hormone alone [ ].

Comparative studies

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 [ ], the former was more potent. There were no clinically relevant differences in safety between the two products and no cases of ovarian hyperstimulation syndrome.

The efficacy and safety of recombinant human follicle-stimulating hormone (r-hFSH) has been compared with that of highly purified urinary follicle-stimulating hormone (u-hFSH HP) in women undergoing ovarian stimulation for in vitro fertilization, including intracytoplasmic sperm injection, in a prospective, randomized study in 278 patients, who were treated with gonadotropin-releasing hormone and then received one of the two formulations in doses of 150 IU/day subcutaneously for the first 6 days; on day 7 the dose was adjusted, if necessary, according to the ovarian response [ ]. Human chorionic gonadotropin (10 000 IU subcutaneously) was administered once there was more than one follicle 18 mm in diameter and two others of 16 mm or larger. Rr-hFSH was more effective than u-hFSH HP in inducing multiple follicular development. There were seven cases (5.0%) of ovarian hyperstimulation syndrome in those given r-hFSH and three (2.2%) in those given u-hFSH HP; this difference was not significant.

Cardiovascular

The effect of androgen suppression therapy used for prostate cancer, prescribed as leuprolide acetate or goserelin, plus flutamide, on the time to fatal myocardial infarction has been studied using pooled trial data [ ]. The data suggest that in men over the age of 65 years, 6 months of androgen suppression therapy reduces the time to fatal myocardial infarction compared with men who have not received therapy. Numbers and data were insufficient to reach further conclusions.

Endocrine

Pituitary apoplexy has previously been reported in association with the use of gonadotropins and analogues. Two case reports remind us of the association. Although pituitary tumors are commonly found on MRI scan and at post mortem, this is an infrequent problem, and routine screening before using these drugs is not justified, although the diagnosis should be considered in a patient reporting typical symptoms.

• A 70-year-old, man developed a visual disturbance 10 days after his first injection of leuprolide 11.25 mg subcutaneously for prostate cancer [ ]. An MRI scan showed a 22 x 26 mm pituitary adenoma. Subsequent histopathology showed a gonadotrophin secreting tumor.

• A few hours after receiving leuprolide 30 mg, a 61-year-old man developed severe headache and neck pain [ ]. A diagnosis of pituitary apoplexy was not made until 2 days later, when he developed ptosis and diplopia. An MRI scan showed a 20 × 18 pituitary adenoma, which was removed and found to be gonadotroph secreting.

Although both these cases were in people with gonadotroph secreting tumors, there have been previous case reports in patients with non-functioning tumors.