General Information: Menotropins are purified combination preparations of the human pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Menotropins are sometimes referred to as human menopausal gonadotropins or hMG. Menotropins are obtained from the urine of postmenopausal women; they are then standardized and purified in accordance with standards established in 1964 by the World Health Organization. Clinical uses include stimulation of spermatogenesis in males with primary or secondary hypogonadotropic hypogonadism and induction of ovulation in anovulatory females. Menotropins are also used in controlled ovarian hyperstimulation protocols for assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF). They are also administered to regulate the timing of ovulation in those patients receiving donor insemination. Menotropins therapy is associated with increased rates of multiple births (>= 20%) compared to the general population (1%). Fifteen percent of multiple gestations are twins; 5% result in triplets or more. In the comparison of menotropins (hMG) to urofollitropin or recombinant FSH preparations, all have similar incidences of major side effects like ovarian hyperstimulation. The FDA first approved menotropins for use in 1975. FDA-approved in August 1999, Repronex® was the first menotropins formulation approved for subcutaneous administration. Menopur®, a urinary derived menotropins product, was FDA-approved in October 2004, and this product is administered via subcutaneous injection. In clinical studies, urinary derived menotropins have comparable pregnancy rates to recombinant FSH products.
Mechanism of Action: Since menotropins are purified preparations of human FSH and LH, the mechanism of action mimics that of the two gonadotropins. However, the FSH activity of menotropins is dramatically greater than that of the LH in the preparation. A small amount of hCG is also present in the preparations. Endogenous FSH and LH are normally secreted from the pituitary every hour in both males and females, and the patterns of secretion are both age and sex dependent. Both FSH and LH are involved in the regulation of ovarian and testicular function.
•Activity in adult females: Endogenous FSH is normally released in abundance during the follicular phase of the menstrual cycle. FSH stimulates the ovarian follicle and controls estrogen release from the granulosa cells of the ovary. Endogenous LH is normally released in a pulsatile fashion in the follicular phase, and then produces an LH surge just before ovulation to promote the final maturation of the oocyte ans corpus luteum. The LH surge stimulates the luteal cells (corpus luteum) to produce progesterone and the thecal cells to produce androgens. Most of the androgens produced are converted to estradiol and other estrogens. In fertility protocols, menotropins are primarily administered to mimic the action of FSH, and administration usually results in follicular growth and maturation. In some circumstances, menotropins therapy is proceeded by or concurrent with GnRH agonists or antagonists to place pituitary hormone regulation in the control of the fertility specialist. To produce ovulation, human chorionic gonadotropin (hCG), which has essentially identical actions as those of LH, is administered after menotropins. Following hCG administration, final luteinization or maturation of the oocytes occurs and either ovulation can ensue, or oocyte retrieval can take place for assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF).
•Activity in adult and adolescent males: Endogenous FSH, along with testosterone, normally stimulates spermatogenesis and androgen-binding protein synthesis in the Sertoli cells of the seminiferous tubules. Endogenous LH stimulates testosterone production in the Leydig cells of the testes. Menotropins, whose primary activity is to provide FSH, are combined with hCG (which acts like LH to stimulate testosterone production) to stimulate spermatogenesis and an increase in testicular volume. Pre-treatment with hCG is required to increase the production of testosterone and the development of secondary sex characteristics prior to the coadministration of menotropins. Once initiated, it takes 70—80 days for germ cells to reach the spermatozoal stage; several months of combination treatment are usually required until adequate sperm counts are produced.
Pharmacokinetics: Menotropins are administered parenterally either as intramuscular (IM) injections, or for select products, as subcutaneous (SC) injections. Due to their polypeptide nature, gonadotropins are quickly destroyed in the gastrointestinal tract. The exact distribution and metabolism of menotropins have not been elucidated. Based on the kinetics of endogenous gonadotropins, the terminal half-life of LH is roughly 0.5—4 hours.
Subcutaneous Route: Based on the ratio of FSH maximum concentrations and the area-under-the-curve, SC administration of menotropins is not bioequivalent to IM administration. Compared to IM administration, SC administration increases the Cmax and AUC of FSH by 35% and 20% respectively. The median time to reach peak FSH concentrations is 12 hours for SC dosing. The mean elimination half-life of FSH is 53.7 hours following single dose SC administration.
For the stimulation of spermatogenesis in males with primary or secondary hypogonadotropic hypogonadism and resultant oligospermia: NOTE: Pretreatment with human chorionic gonadotropin (HCG) is required prior to combination with menotropins. Various HCG dosages have been used; continue for a period sufficient to achieve normal serum testosterone. HCG pretreatment may require 3 to 6 months (see HCG monograph).
Intramuscular dosage or Subcutaneous dosage (combined menotropins/hCG therapy):
Adult males: Various dosage regimens have been advocated. The following alternative regimens have been employed; however, the total dosage and duration of treatment may vary widely. ONE REGIMEN; hCG 1,000 to 1,500 USP units IM/subcutaneously in combination with menotropins 75 to 150 international units IM/subcutaneously 3 times per week, at separate injection sites. ALTERNATIVELY; hCG 2,000 USP units IM/subcutaneously 2 times per week in combination with menotropins 75 to 150 international units IM/subcutaneously 3 times per week, at separate injection sites. Continue chosen regimen for at least 4 months to ensure detection of spermatozoa in the ejaculate and to increase testicular volume. Most men in clinical trials to date are noted to have sperm output by 6 months; target goals are reached with a median 9 months of treatment.
For the treatment of infertility in females: NOTE: During any protocol for ovulation induction, menotropins must be discontinued and hCG must not be given if the ovaries are abnormally enlarged, more than 3 follicles of 15 mm size are present, an ovarian cyst is present, or the serum estradiol exceeds 2000 pg/mL. Consult specialized references for specific fertility protocols.
For the induction of follicle development in women who have received GnRH agonist or antagonist pituitary suppression and who are enrolled in protocols for in vitro fertilization (IVF) or other assisted reproductive technology (ART):
Subcutaneous dosage: Adult females: 225 international units of FSH/LH activity given subcutaneously once daily initially. Urofollitropin may be administered together with menotropins with a total initial dose not to exceed 225 international units subcutaneously (150 international units urofollitropin, 75 international units menotropins OR 75 international units urofollitropin, 150 international units menotropins). Based on clinical monitoring, subsequent dosing may be adjusted according to patient response. Adjust dose by no more than 150 international units/day every 2 days. Max dose: 450 international units/day (menotropins alone or in combination with urofollitropin); duration beyond 20 days in any cycle is not recommended. Discontinue when the patient response is appropriate. Give hCG 1 day after the last dose of menotropins. Oocyte retrieval is usually performed 34 to 36 hours later, before ovulation can occur.1
Maximum Dosage Limits: No specific maximum dosage limit recommendations are available. Dosage regimens of menotropins depend upon the patient's age, sex, condition being treated, and the prescribing clinician's judgment. Therefore, doses vary widely and must be carefully individualized.
General Administration Information: NOTE: Menotropins (hMG) should be used only by health care prescribers who are experienced in managing endocrine or fertility disorders and only in facilities where appropriate clinical and endocrinology evaluations are available.
- When administered via subcutaneous injection, menotropins and urofollitropin may be mixed and administered in the same syringe.1
- Subcutaneous injections of menotropins should be made into the lower abdomen. Injection into the thigh is not recommended unless the lower abdomen is not usable because of scarring, surgical deformity or other medical conditions.
- Inject subcutaneously taking care not to inject intradermally.
- Alternate sides with each dose administration.
Contraindications: Menotropins are contraindicated for use in any patient with a prior history of menotropins hypersensitivity.
Menotropins are not indicated for use in children.
Menotropins will only be effective at inducing ovulation in women with an intact ovarian response. The presence of any cause of infertility other than anovulation contraindicates the use of menotropins unless the patient is a candidate for assisted reproductive technology (ART) procedures like in-vitro fertilization (IVF). Patients with organic intracranial lesions such as pituitary adenoma or other pituitary tumor or primary ovarian failure (as indicated by increased serum gonadotropin concentrations) will not respond to menotropins treatment and therefore it's is contraindicated. Menotropins treatment is also contraindicated in patients with uncontrolled thyroid disease or untreated adrenal insufficiency.
Because fertility protocols that include menotropins may stimulate the growth of hormonally dependent tissues in women, menotropins administration is contraindicated for use in patients with abnormal or dysfunctional uterine bleeding of undetermined origin. Neoplasm (e.g., ovarian or endometrial carcinoma) should be ruled out before use. Menotropins are contraindicated for use in patients with sex hormone dependent neoplastic disease of the reproductive tract and accessory organs (e.g., ovarian cancer, uterine cancer, breast cancer, etc.). Endometrial growth may be stimulated by these fertility protocols; they should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis.
Prior to initiation of menotropins treatment in women, a full gynecologic exam and endocrine assessment should be performed. Except for those patients enrolled in ART programs, this should include an exam to rule out tubal pathology. Menotropins are contraindicated in patients with ovarian enlargement or a preexisting ovarian cyst that is not due to polycystic ovarian syndrome (PCOS). Menotropins therapy should not be initiated until the diagnostic cause of the cyst or enlargement has been determined and ovary size has returned to normal. Menotropins are contraindicated for use in patients with abnormal or dysfunctional uterine bleeding of undetermined origin. Neoplasm (e.g., ovarian or endometrial carcinoma) should be ruled out in such patients. Because menotropins may stimulate endometrial growth, they should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis.
All female patients undergoing menotropins treatment should be instructed to report symptoms of ovarian enlargement, including abdominal pain or pelvic pain; nausea; vomiting; ascites (fluid and distension in the abdomen); or weight gain immediately. The current cycle of fertility agents should be halted if ovarian enlargement or ovarian hyperstimulation syndrome (OHSS) occurs or if an ovarian cyst develops; maximal ovarian enlargement may not be evident until several days after fertility drug discontinuation. Sexual intercourse should be avoided to limit trauma risk. hCG administration should not occur in these patients or in patients with symptoms or signs of abnormal ovarian enlargement on the last day of menotropins therapy. However, withholding of hCG does not ensure that OHSS will not occur. Fertility therapy should not be reinstated until ovary size has returned to normal. Complete pelvic exams, including pelvic ultrasounds, should be repeated in all female patients during and prior to each fertility drug cycle. Some patients with polycystic ovary syndrome (PCOS) are unusually sensitive to gonadotropins and may have an exaggerated response to ovarian hyperstimulation protocols.
Menotropins are used in the treatment of infertility and are classified in FDA pregnancy category X and thus are contraindicated after conception has occurred. Limited data are available regarding the use of menotropins in human gestation, and the potential for serious fetal harm cannot be excluded. Therefore, pregnancy should be ruled out prior to the administration of menotropins with each fertility treatment course. In addition to potential effects on the fetus, including congenital malformation, protocols using menotropins inherently increase the risk of multiple gestation and the risks associated with such pregnancies. The rate of spontaneous abortions in women who become pregnant after receiving menotropins may be increased; reasons have not been established.1
Menotropins should be used with caution in lactating mothers who are breast-feeding their infants. Most endogenous gonadotropins are found in breast milk or tissues to some degree. It is neither known whether exogenous menotropins are distributed into breast milk, nor what effect they would have on the feeding infant.1
Rarely, thromboembolic events have been reported in females receiving medications for fertility protocols.1 should be used with extreme caution in those patients with a a personal or family history of thrombophlebitis or other active thromboembolic disease, and in patients with severe obesity. These patients may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins. This warning does not apply to the use of menotropins treatment in males.
Clinical studies of menotropins for the treatment of infertility in women typically do not include a sufficient number of geriatric females. Use with caution in elderly females who are undergoing assisted reproductive technology (ART) procedures.
Drinking alcoholic beverages, including ethanol intoxication, or tobacco smoking are two lifestyle choices that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should avoid excessive alcohol or tobacco consumption while pursuing fertility therapies such as menotropins.
Menotropins is contraindicated in men with normal serum gonadotropin concentrations, which indicates normal pituitary function; in primary testicular failure (indicated by increased serum gonadotropin concentrations); and in infertility other than that resulting from hypogonadotropic hypogonadism.
Pregnancy: Menotropins are used in the treatment of infertility and are classified in FDA pregnancy category X and thus are contraindicated after conception has occurred. Limited data are available regarding the use of menotropins in human gestation, and the potential for serious fetal harm cannot be excluded. Therefore, pregnancy should be ruled out prior to the administration of menotropins with each fertility treatment course. In addition to potential effects on the fetus, including congenital malformation, protocols using menotropins inherently increase the risk of multiple gestation and the risks associated with such pregnancies. The rate of spontaneous abortions in women who become pregnant after receiving menotropins may be increased; reasons have not been established.1
Breast-feeding: Menotropins should be used with caution in lactating mothers who are breast-feeding their infants. Most endogenous gonadotropins are found in breast milk or tissues to some degree. It is neither known whether exogenous menotropins are distributed into breast milk, nor what effect they would have on the feeding infant.1
Interactions: Black Cohosh, Cimicifuga racemosa: (Major) Due to a lack of data regarding maternal or fetal safety and efficacy, the FDA currently recommends that patients who are pregnant or who are trying to get pregnant, such as patients receiving fertility agents, should not take Black cohosh, Cimicifuga racemosa without explicit instruction to do so by their qualified health care provider, midwife, or gynecologist/obstetrician. 2 3 4
Adverse Reactions: Infrequent reports of both benign and malignant ovarian neoplasms exist in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.5 Some observational studies and a number of case reports gave rise to the speculation that infertility treatments, like menotropins, might enhance the risk of secondary malignancy in women (i.e., breast cancer or ovarian cancer). However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Case reports and observational studies suggesting an association of cancer to fertility treatments rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population.6 As such, the current data do not support an association between the use of fertility drugs and increased cancer risk.
Data suggest that teratogenesis might occur if menotropins are inadvertently continued in early pregnancy. It is important that menotropins therapy be continued in subsequent fertility cycles only after pregnancy has been ruled out and normal withdrawal bleeding (menses) has occurred. The incidence of congenital defects among completed pregnancies in manufacturer reported studies are estimated to be 1.7%, which approximates that of the normal population. The spontaneous abortion rate of pregnancies following menotropins therapy may be as high as 25%, but reasons for the increased fetal death rates versus the normal population have not been established. In addition to potential effects on the fetus, protocols using menotropins in females inherently increase the risk of multiple gestation (>= 20%) and the risks associated with such pregnancies. There is less information available on the effects of menotropins use in men and resultant infant outcomes.5
Among recipients of menotropins, <= 2.8% had diarrhea, 4—12% had nausea, <= 4.2% had vomiting, 5—17.6% had abdominal pain or cramping, <= 3.2% had back pain, and <= 1.6% had constipation.15 Nausea, vomiting, diarrhea, and abdominal pain may also be symptoms of the ovarian hyperstimulation syndrome.
The use of menotropins in combination with human chorionic gonadotropin (hCG) at therapeutic doses is generally well tolerated. The appearance of side effects related to menotropins may vary with dosage administered, gender, and reason for therapeutic use. Among menotropins recipients, 5.2—34.1% had headache, 2.4% had migraine, 2.6—2.8% had malaise, 0.6—2.6% had hot flashes, and 2.6% had dizziness. Fatigue may also occur.51
Allergic reactions with menotropins are rare (< 1%) but may be either local or systemic in nature. Reactions have included anaphylactoid reactions, angioedema, facial or laryngeal edema, dyspnea or shortness of breath (1—2.1% of patients), rash (unspecified), and generalized urticaria. Flushing (2.4%) has also been reported. The relationship of these symptoms to uncharacterized urinary proteins is uncertain. Febrile reactions suggestive of allergic response have been reported after the administration of menotropins. Reports of flu-like symptoms have been indicative of an allergic response in some individuals and may include fever, chills, myalgia, arthralgia, nausea, headache, and malaise.51
An injection site reaction may occur and may include pain, ecchymosis, swelling, irritation, mild erythema, or pruritus, particularly with subcutaneous administration of menotropins. Local rash may occur but does not usually preclude further medication use. Subcutaneous administration of Menopur led to injection site pain in 5.4% of patients and an injection site reaction in 9.6—11.8% of patients. Injection site edema or reaction was noted in 8.3% of Repronex SC recipients. In contrast, of Repronex IM recipients, 2% had an injection site reaction, and 1% had injection site edema. In some protocols, patient acceptability of injections is improved with subcutaneous injections because of the ease of self-administration. Patient tolerability is also improved by the use of highly purified menotropins.51
Among menotropins recipients, 1.8—2.6% had mastalgia or breast tenderness.51 Up to 30% of adult and adolescent men may complain of gynecomastia with the combination treatment of hCG/menotropins. The mechanism underlying the gynecomastia is thought to be due to the secretion of estrogen from the Leydig cells in response to the administration of hCG. The lowest dosage of hCG that maintains the patient's serum testosterone levels within the normal range may be helpful in limiting this unwanted side effect during combination treatment.
Mild to moderate uncomplicated ovarian enlargement that may be accompanied by abdominal distension and/or abdominal discomfort occurs in approximately 5—10% of those treated with menotropins and hCG and generally regresses without treatment within two or three weeks. Adnexal torsion as a complication of ovarian enlargement has also been reported during menotropins therapy. Pelvic pain, cramps, or discomfort was noted in 0.4—3.9% of patients. Further, an enlarged abdomen was noted in 2.1—6%, and 3.2—9.2% had abdominal fullness. In order to minimize the hazard associated with the occasional abnormal ovarian enlargement, use the lowest dose consistent with expectation of good results. Careful monitoring of ovarian response can further minimize the risk of overstimulation.5 Pelvic examinations should be performed in patients who complain of abdominal discomfort (pelvic pain) during therapy. Menotropins must be discontinued and hCG must not be given if the ovaries are abnormally enlarged, > 3 follicles of 15 mm size are present, an ovarian cyst is present, or the serum estradiol concentration exceeds 2000 pg/ml, in order to prevent progression to ovarian hyperstimulation. Further therapy should be withheld until resolution of the signs and symptoms and until the ovary is no longer enlarged. If substantial ovarian enlargement occurs after ovulation, sexual intercourse should be prohibited because of the risk of hemoperitoneum secondary to ruptured ovarian cysts and the increased risk of ovarian hyperstimulation should conception occur. Laparoscopy is rarely needed. Ovarian enlargement or ovarian cyst formation may be more likely to occur in patients with polycystic ovary syndrome.
Thromboembolic events such as thromboembolism both in association with and separate from the ovarian hyperstimulation syndrome have been reported after menotropins therapy. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the extremities. Sequelae of such events have included venous thrombo-phlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have been fatal.5 Certain patients with other risk factors for thromboembolism may be at higher risk.
Menotropins therapy can result in ovarian hyperstimulation syndrome (OHSS). In trials, OHSS was noted in 2—13.2% of patients. Do not administer hCG if the ovaries are abnormally enlarged on the last day of menotropins therapy. OHSS is a medical event distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS develops rapidly; therefore, follow patients for at least two weeks after hCG administration. Usually, OHSS resolves spontaneously with the onset of menses. If OHSS occurs, discontinuation of therapy and hospitalization are required. A physician experienced in the management of the syndrome or who is experienced in the management of fluid and electrolyte imbalances should be consulted. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days after treatment. The syndrome results from an apparent increase in vascular permeability that can cause rapid fluid accumulation in the peritoneal cavity, thorax, and potentially the pericardium. The pathogenesis of this syndrome is still unknown but probably results from the production and secretion of several substances (i.e., prostaglandin, cytokines, vascular endothelial growth factor, and activation of the ovarian-renin-angiotensin system) in response to the stimulation of ovulation. Patients have exhibited increased plasma angiotensin-converting enzyme (ACE) activity in association with this syndrome. Some early warning signs include severe abdominal pain and distention, pelvic pain, nausea/vomiting, diarrhea, and weight gain. OHSS usually peaks within 7—10 days and may resolve spontaneously with menses onset. Severe cases produce clinical signs such as gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. Other reported symptoms of OHSS include pericardial effusion, anasarca, hydrothorax, acute abdomen, elevated hepatic enzymes, hypotension, renal failure (unspecified), pulmonary edema, intraperitoneal (hemoperitoneum) and ovarian hemorrhage, deep venous thrombosis, stroke, torsion of the ovary, and acute respiratory distress. Elevated urinary steroid levels, electrolyte imbalances such as hyperkalemia, hypovolemia, hemoconcentration, and hypoalbuminemia may also occur. Hemoconcentration, hypovolemic shock, or thrombotic events may be fatal. Abdominal and pelvic examination should be done carefully, if at all, in severe cases of OHSS due to the fragility of the enlarged ovaries. Intercourse should be prohibited in cases of severe ovarian enlargement where the onset of OHSS might occur. Conception may result in progression to the severe form of OHSS. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs.15
Sinus tachycardia, tachypnea, atelectasis, acute respiratory distress syndrome (ARDS), and increased cough (1.6—2.6%) have been reported during menotropins therapy.51
Vaginal bleeding was noted in 3.1—7.9% of patients who received menotropins.5
How is this medication best taken? This medicine is for injection under the skin. If you get this medicine at home, you will be taught how to prepare and give this medicine. Use exactly as directed. Take your medicine at regular intervals. Do not take it more often than directed. It is important that you put your used needles and syringes in a special sharps container: do not put them in a trash can. If you do not have a sharps container, call your local pharmacy or healthcare provider to get one.
What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
Storage: Keep this medicine in a refrigerator at 2°-8°C (36°-46°F). Keep all medicine out of the reach of children. Throw away any unused medicine after the expiration date. Do not flush unused medications or pour down a sink or drain.
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- 3. Dog TL, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief. Menopause 2003;10:299-313. Review.
- 4. Dugoua JJ, Seely D, Perri D, et al. Safety and efficacy of black cohosh (Cimicifuga racemosa) during pregnancy and lactation. Can J Clin Pharmacol 2006;13:e257-61.
- 5. a. b. c. d. e. f. g. h. i. j. k. l. Repronex (menotropins) injection package insert. Suffern, NY: Ferring Pharmaceuticals Inc.; 2007 Apr.
- 6. Potashnik G, Lerner-Gava L, Genkin L, et al. Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 1999;71:853-859.