Pergonal

Introduction

Pergonal is a fertility drug used to treat fertility issues in women, especially women who are anovular and oligoovular. Pergonal is considered a menotropin, which is a mixture of follicle-stimulating hormones (FSH) and Luteinizing hormone (LH). Pergonal is obtained from the urine of post-menopausal women. Although these women no longer have functional ovaries to regulate production of stimulating hormones, these women’s glands still produce FSH and LH in their urine. This drug is then given to pre-menopausal women to stimulate follicle formation. The drug is often given with Human Chorionic Gonadotropin (hCG). The hCG then provides an LH surge, which then causes ovulation. In rare cases, this drug can also be used in males to stimulate the production of sperm.

History

In 1906, the biotechnology company Serono was formed in Geneva, Switzerland. The company gained its reputation in 1949, when the scientist Dr. Piero Donini became the first person to extract and purify a human gonadotropin. His discovery provided the basis for the development of the fertility drug Pergonal. Pergonal is a human menopausal gonadotropin (hMG) which is prepared through purification of a urine extract from post-menopausal women. It contains equal parts of the human gonadotropins FSH and LH. Pergonal can be used in both men and women to treat infertility issues, although it is primarily used in women.

Methods of Administration in Women for Fertility Treatment

The methods of use for Pergonal vary. Patients are treated first with leuprolide acetate injections first. Leuprolide acetate (LA) is an antagonist to GnRH. The standard dosage amount of LA is one milligram (mg) per day. The LA treatment may be started as early as one week before expected menses. If patients do not begin menses within at least 20 days of starting the LA injections other treatments may be sought. Seven days after menses has started injections of pergonal are commenced. Pergonal may be given in subcutaneous injections in the right or left lower abdomen or it may be administered in intramuscular injections in the right or left buttock. The patient may give the injections to themselves after training. Standard dosage of Pergonal is 225 International Units (IU). The injections of Pergonal are given daily for five consecutive days. On the sixth day, the patient is evaluated for estradiol levels, number of follicles and development of follicles. If the patient was not responsive to the initial five injections of Pergonal (for example multiple follicles bigger than 14 mm), daily injections of Pergonal may continue for up to seven more days. In total, the patient may receive 12 injections. The dosage may be increased every other day by 75–150 IU. Once the patient has had satisfactory response, the patient is given 10,000 USP units of human chorionic gonadotropin (hCG). Approximatly 30 hours after the injection of hCG, attempts to fertilize may be initiated either via in vitro fertilization or naturally.

Example of Administration in Women for Fertility Treatment

Side Effects

Biochemical Pathway: cAMP Second Messenger System

The Pergonal (LH and FSH) binds to its receptor on theca interna cell in female. A G-protein then associates with the receptor which then interacts with the Adenylate Cyclase (Adenylate C.) protein. The Adenylate Cyclase converts ATP into cyclic AMP (cAMP). The cAMP binds to Protein Kinase A (PKA) which is made of two subunits. One subunit is called the Regulatory subunit (R) and the other is a catalytic (C) subunit. The binding of cAMP to PKA causes the two subunits to separate. The C subunit does multiple things. The C subunit catalyses cholesterol uptake into the mitochondria. It also enters nucleus and phosphorylates (PO4) specific proteins such as histones on DNA. This phosphorylation of the histones, causes the production or transcription of specific mRNA. The mRNA leaves nucleus and goes into cytoplasm and to the Rough Endoplasmic Reticulum (RER). In the RER the mRNA are translated into proteins. These proteins produce enzymes involved in cholesterol uptake in mitochondria, and conversion into pregnenolone. These factors, among others are used by the smooth endoplasmic reticulum (SER), to form Estrogen.

Research related to Pergonal

Comparison of Highly Purified FSH (Metrodin-High Purity) with pergonal for IVF Superovulation- J.S. Bagratee, G. Lockwood, A. Lopez Bernal, D.H. Barlow, and W.L. Ledger.

Background

Gonadotropin are used clinically to treat infertility, gonadotropin contain a mixture of FSH-follicle stimulating hormone and LH luteinizing hormone. In this particular study, the effects of two gonadotropin hMG-human menopausal gonadotropin (Pergonal), and Metrodin-HP (a high purity follicular stimulator) with respect to Amenorrhea ( lack of menstrual cycle) and hypothalamic and pituitary malfunction.
Gonadotropin therapy is a widely used protocol along with pituitary desensitation which has been approved and accepted prior to IVF-in vitro fertilization (Bagratee et al, 1998).

The Study

This particular study was executed to compare the reproductive performance of Metrodin-HP in contrast to hMG-Pergonal for ovarian stimulation in IVF.

Materials and Methods

Patients were allotted to receive either hMG or Metrodin, it was assigned nonrandom due to fact that some patients have undergone similar methods in prior trial, thus they chose the treatment that they were familiar with. Dosage was of hMG or Metrodin-HP was assigned according to age, weight, and early follicular phase gonadotropin concentration (blood plasma ~30pg/mL). In order to check on the follicles, ultrasounds were used to determine follicular diameter, once they reached a threshold of 16mm or greater they were collected by transvaginal wash procedure.

Table 1 Stimulating Regimen

Collected eggs were incubated for 5-6hr prior to being inseminated with 2.0E5 sperm/mL, Oocytes were later incubated and observed 18hrs later for the presence of 2 pronuclei; once transferred a pregnancy test were administered 14 days later.

Table 2 Outcomes

Statistical Results and Relevance

A P value less than 0.05 was considered to be statistically significant.The statistical procedure consisted of averages, standard deviation, 2 tailed t test or chi square test as necessary.
Overall results showed that in the Met-HP group showed that 26% had live births compared to pergonal (hMG) with 18.5% with a P=0.22 Not significant. However, data showed that Met-HP is as effective as hMG in an IVF ovulation inducing protocol; due to the study being nonrandom it must be analyzed in a carefully manner before assuming clinical significance, cost and procedure must be also be taken into consideration, Met-HP is a new treatment that involves less cost, while hMG is a more common treatment known to be more costly.

Subcutaneously Administered Repronex in Female Patients Undergoing in Vitro Fertilization is as Effective and Well Tolerated as Intramuscular Menotropin Treatment. -Gocial, B., et al.

Menotropin products, which are partially purified preparations of gonadotropins were given as daily intramuscular injections for 5-12 days induce follicular development. The study used 186 patients deemed infertile due to various causes. Repronex is a relatively new product compared to Pergonal. The intent of the study was to determine if Repronex, administered subcutaneously, was as effective and safe as the IM administration of Repronex or Pergonal.
The protocol for treatment was as is on the calendar visible on this website. Each patient was randomly assigned to receive Repronex Subcutaneous (SC), Repronex intramuscular (IM) or Pergonal IM. According to this study, SC injections are more desirable because of ease. The initial injections were all at a dosage of 225 IU, per day. Subcutaneous injections were administered in the right and left lower abdomen or intramuscularly in the left or right buttock. After five days of menotropin injections follicle presence and size was measured. If patients had satisfactory response hCG was given approximately 30 hours later or menotropin injections were continued. The menotropin injections were not performed for more than 12 days. If the patients’ blood serum E2 rose to or above 6,000 pg/mL the patient was discontinued from the study.
When comparing the Repronex treatments to the Pergonal IM, no statistical difference was found between patients who received the hCG. Fifty-five patients receiving the Repronex SC patients received hCG, 61 patients receiving the Repronex IM received hCG and 56 Pergonal IM patients received hCG.
A statistically significant difference among the treatment groups was found when comparing the occurrence of ovarian cysts. In Repronex SC patients, 46.7% had induced ovarian cysts, compared to the Pergonal IM group who only had 26.2% of patients with induced ovarian cysts (P<.02).
The number of patients with continuing pregnancies was also found to be statistically greater in the group of patients receiving the Repronex SC (28 patients) than those receiving the Pergonal IM (19 patients; P=.046).
Multiple births were observed but not significant among treatments. 15 of the 55 Repronex patients receiving the injections SC had multiple births. In patients administered Repronex IM, 10 out of 61 experienced multiple births. 14 multiple births were recorded out of 56 patients receiving the Pergonal via intramuscular injections.
It would be interesting to understand why the conductors of this study did not choose to also study the effects of administering Pergonal subcutaneously. Despite the higher instance of ovarian cysts in the Repronex SC patients, it was still concluded in this study that the Repronex was as efficient and safe as the IM injections.

References

Fleming, R., et al. "Purified Urinary Follicle Stimulating Hormone Induces Different Hormone Profiles Compared with Menotrophins, Dependent upon the Route of Administration and Endogenous Luteinizing Hormone Activity." Human Reproduction 11.9 (1996): 1854-8.

Gocial, B., et al. "Subcutaneously Administered Repronex* in Female Patients Undergoing in Vitro Fertilization is as Effective and Well Tolerated as Intramuscular Menotropin Treatment." Fertility and sterility 74.1 (2000): 73-9.

Kemmann, E., et al. “Induction of Ovulation with Menotropins in Women with Polycystic Ovary Syndrome”. AM. J. Obstet. Gynecol. 141:58, 1981.
Nichols, J., et al. "Subcutaneously Administered Repronex (R)(a) in Oligoovulatory Female Patients Undergoing Ovulation Induction is as Effective and Well Tolerated as Intramuscular Human Menopausal Gonadotropin Treatment." Fertility and sterility 76.1 (2001): 58-66.

http://www.umm.edu/altmed/drugs/menotropins-081100.htm University of Maryland.

Senger, P.L. “Pathways to pregnancy and parturition”. 2nd Revised Edition. 2005.

D. Paduch, J. Kiper. “Efficacy of clomid, arimidex, and androgel in normalizing testosterone in young hypogonadal men presenting with infertility and sexual dysfunction” Fertility and Sterility, Volume 88, Issue null, Pages S75-S75

Bay Area Fertility and Gynecology Medical Group: Online.Internet Available: http://www.ihr.com/bafertil/articles/pergmetr.html
Kiplinger Features "The Agonizing Price of Infertility" Online.Internet. 1996 May
Available: http://www.kiplinger.com/magazine/may96/inferti.html

Alcivar, A. A., R. R. Maurer, and L. L. Anderson. Endocrine Changes in Beef Heifers Superovulated with Follicle-Stimulating Hormone or Human Menopausal Gonadotropin. Journal of Animal Science, 1992. Web. 21 Oct. 2009.

"Pergonal consumer information from Drugs.com." Drugs.com | Prescription Drugs - Information, Interactions & Side Effects. Web. 20 Nov. 2009. <http://www.drugs.com/cons/pergonal.html>.

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Lecture 6b from University of Wisconsin-Madison, DS/AS 434 class website http://www.ansci.wisc.edu/jjp1/ansci_repro/index.html