VA Class:HS400
ATC Class:G03GA
Menotropins is a purified preparation of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are human pituitary gonadotropins extracted from urine of postmenopausal women.1, 3, 14
Assisted Reproductive Technology Programs
Human menopausal gonadotropins (hMG), also referred to as menotropins, is used as a component of infertility regimens to induce multiple follicular maturation and pregnancy in ovulatory women undergoing controlled ovarian hyperstimulation during assisted reproductive technology (ART) programs such as in vitro fertilization (IVF).1, 4, 14
A controlled ovarian hyperstimulation regimen used during ART generally consists of pituitary desensitization with a gonadotropin-releasing hormone (GnRH) agonist (e.g., nafarelin†, leuprolide†) or GnRH antagonist (e.g., ganirelix, cetrorelix), a follicle-stimulating agent (e.g., menotropins, urofollitropin, recombinant follitropin alfa), an agent to induce ovulation (e.g., human chorionic gonadotropin [hCG]), and an agent to support the luteal phase (e.g., progesterone).4, 5, 14 Both GnRH agonists and antagonists prevent premature oocyte release and luteinization of the targeted stimulated cycle in order to obtain a greater oocyte yield and higher pregnancy rates.4, 5, 14 During the follicular phase of the stimulated cycle, a follicle-stimulating agent is given to induce development of a number of follicles.1, 4, 5, 14 At the end of the stimulation phase, hCG is typically used as a surrogate luteinizing hormone (LH) surge to induce final oocyte maturation before oocyte retrieval in assisted reproduction.1, 3, 4, 5, 14 Progesterone is generally used to support embryo implantation and early pregnancy by supplementing corpus luteal function.4, 5, 14, 16
Highly purified menotropins (Menopur®) has been shown to be as effective as recombinant follicle-stimulating hormone (FSH) in terms of ongoing clinical pregnancy rates.2 However, additional studies are needed to compare the safety and clinical efficacy of various urinary and recombinant gonadotropin products.11, 12, 20 A less-purified menotropins preparation (Repronex®) containing higher amounts of extraneous urinary proteins previously was used for multiple follicular development and ovulation induction as part of an ART program or in women with functional anovulation (i.e., secondary to pituitary insufficiency and not due to primary ovarian failure); this preparation is no longer commercially available in the US.7, 24 Variable efficacy of gonadotropin products has been reported, possibly due to lack of control of baseline characteristics, differences in treatment dose and duration, and post-randomization management in clinical trials.14, 20 Data are lacking on the advantages of using one type of gonadotropin over another in different patient subsets.10, 14 The heterogeneity of infertility conditions and patients' characteristics necessitates the individualization of controlled ovarian hyperstimulation regimens.12, 13 Additional factors that should be considered when choosing a gonadotropin include cost, safety, patient acceptability, and drug availability.19 The ideal controlled ovarian hyperstimulation protocol should attain the optimum number of oocytes while minimizing risks and treatment burden.13
Women approved for treatment with gonadotropins must have ovaries that respond to FSH and LH stimulation.4 Candidates for menotropins treatment must be given a complete gynecologic and endocrinologic evaluation to diagnose the cause of infertility.1 Evaluation of the fertility potential of the male sexual partner also should be performed.1 The possibility of primary ovarian failure and of pregnancy must be excluded before initiating treatment with menotropins.1, 4 (See Cautions: Contraindications.)
Safety and efficacy of menotropins for the development of multiple ovarian follicles and pregnancy in ovulatory women as part of an ART cycle have been established principally in a randomized, open-label, multicenter, multinational comparative clinical trial that was designed to demonstrate noninferiority of highly purified menotropins (Menopur®) compared with recombinant FSH (follitropin alfa [Gonal-F®]).1, 2, 7 The primary end point was ongoing pregnancy rate, which was defined as ultrasound visualization of the gestational sac with a fetal heart beat at least 10 weeks after embryo transfer.1 The trial enrolled 781 subfertile women (infertility for more than 1 year [except those with bilateral tubal occlusion and/or male factor infertility]) 18-38 years of age undergoing IVF or intracytoplasmic sperm injection (ICSI) treatment cycles.2, 7 All eligible patients received pituitary down-regulation treatment with a GnRH agonist administered either as a daily injectable or depot formulation during the midluteal phase.1, 2, 7 Patients without ovarian cysts (confirmed by ultrasound) who had serum estradiol concentrations below 200 pmol/L then self-administered either 225 units of follitropin alfa or 225 units of highly purified menotropins subcutaneously for 5 days.1, 2, 7 On day 6, dosage of the drugs was adjusted (up to a maximum of 450 units daily based on individual patient response) and treatment continued for up to 20 days until criteria for ovulation induction with hCG (3 or more follicles with a diameter of at least 16 mm and/or estradiol concentrations of 1000 pmol/follicle) were met.1, 2, 7 Patients with a poor response, defined as failure to meet hCG criteria within a 20-day period of stimulation or requiring more than 450 units daily of follitropin alfa or highly purified menotropins, were withdrawn from the trial.2 Once the specified criteria for ovulation induction were met, patients received 5000-10,000 units of hCG administered either subcutaneously or IM.2, 7 Ovum retrieval was conducted 32-42 hours after the administration of hCG.2 Fertilization (i.e., IVF and ICSI) was performed according to the trial center's standard practice.2 The luteal phase was supported with progesterone also according to the trial center's standard practice.2 Approximately 1-3 normally developed embryos were transferred and pregnancy tests (serum or urine) were performed 2-3 weeks posttransfer.2 The European formulation of menotropins used in this clinical trial has been shown to be bioequivalent to the formulation currently marketed in the US (Menopur®).7
There was no substantial difference in ongoing clinical pregnancy rate between highly purified menotropins and follitropin alfa (event rate 23 versus 21%).1, 7 Both treatment groups were comparable with respect to adverse effects and tolerability.2
Reconstitution and Administration
Treatment with menotropins should only be initiated by clinicians who are experienced in infertility treatment; appropriate monitoring facilities are required for gonadotropin treatment.1
Menotropins is administered by subcutaneous injection into the lower abdominal region, 1-2 inches below the navel; injection sites should be rotated and alternated between left and right sides.1, 14, 29
When injecting menotropins subcutaneously, the entire length of the needle should be inserted into a skinfold created by the thumb and the forefinger; the skinfold should be released when withdrawing the needle.1, 29
Menotropins may be self-administered by the patient.1, 29 (See Menopur® patient information and instructions for use.) Menotropins may be administered together with urofollitropin (Bravelle®) in the same syringe.1, 9, 23, 29
Commercially available vials of menotropins should be stored at 3-25°C and protected from light.1
Menotropins is commercially available as a lyophilized powder that requires reconstitution with 0.9% sodium chloride injection (supplied by manufacturer) prior to administration.1, 14, 29 The drug is reconstituted by adding 1 mL of 0.9% sodium chloride injection to a vial labeled as containing 75 units each of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity.1 The vial should be gently swirled (not shaken) until all the powder has dissolved.1, 29 If more than 1 vial is required to prepare the intended dose or if menotropins is to be mixed with urofollitropin (Bravelle®) in the same syringe, the reconstituted solution of menotropins may be used (instead of 0.9% sodium chloride injection) to reconstitute up to 5 more vials of drug (menotropins or urofollitropin).1, 23, 29 Reconstituted solutions of menotropins should be used immediately and any unused portion should be discarded.1, 14
The manufacturer-supplied instructions for use should be consulted for additional detailed information on reconstitution and administration of Menopur®.1, 29
Dosage of menotropins is expressed in international units (IU, units) of FSH and LH activity; each unit of menotropins represents 1 unit of FSH and 1 unit of LH activity.1
Assisted Reproductive Technology Programs
Dosage of menotropins required to produce follicular maturation must be individualized for each patient.1, 8 To minimize the risk associated with abnormal ovarian enlargement in women receiving menotropins, the drug should be administered at the lowest possible effective dosage.1, 8
For follicular stimulation in women who have received a gonadotropin-releasing hormone (GnRH) agonist for pituitary suppression as part of their ovulation induction regimen for in vitro fertilization (IVF), the recommended initial dosage (beginning on cycle day 2 or 3) of menotropins is 225 units daily for the first 5 days of treatment.1 Subsequently, based upon the woman's ovarian response (as determined by ultrasound evaluation of follicular growth and on serum estradiol concentrations), the daily dosage of menotropins may be adjusted in increments or decrements not exceeding 150 units, and dosage adjustments should be made no more frequently than every 2 days.1
An initial menotropins dosage of 225 units daily also has been used in women who will receive a GnRH antagonist † for pituitary suppression.21, 22
Menotropins may be administered with urofollitropin (e.g., Bravelle®) as a part of an ovulation induction regimen for IVF; the total initial daily dosage when the drugs are combined should not exceed 225 units (menotropins 150 units and urofollitropin 75 units, or menotropins 75 units and urofollitropin 150 units).1, 23 The maximum daily dosage of menotropins or menotropins in combination with urofollitropin should not exceed 450 units.1, 23
Once adequate follicular development is evident (estimated by ultrasound and/or serum estradiol concentrations), human chorionic gonadotropin (hCG) should be administered1 (generally 1 day after the last dose of menotropins) to induce final follicular maturation in preparation for oocyte retrieval.4, 5 Treatment with menotropins should not exceed 20 days.1
The administration of hCG should be withheld in patients where ovarian monitoring suggests an increased risk of ovarian hyperstimulation syndrome (OHSS).1, 8 (See Ovarian Hyperstimulation Syndrome under Cautions: Warnings/Precautions.)
No special population dosage recommendations at this time.1
Known hypersensitivity to menotropins or any ingredient in the formulation.1, 29
Primary ovarian failure (as indicated by high concentrations of follicle-stimulating hormone [FSH]), uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, pituitary disorders), or tumors of the pituitary gland or hypothalamus.1, 29
Abnormal intrauterine bleeding of undetermined origin, ovarian cysts or enlargement of undetermined origin (not due to polycystic ovary syndrome [PCOS]), or sex-hormone-dependent tumors of the reproductive tract and accessory organs.1, 29
Uncomplicated ovarian enlargement has been observed during treatment with gonadotropins, including menotropins.1, 2, 4, 8 Individualization of treatment, use of the lowest effective menotropins dosage, and careful monitoring of ovarian response (ultrasound and measurement of serum estradiol concentrations) can minimize the risk of ovarian overstimulation.1
If the ovaries are abnormally large on the last day of menotropins treatment, administration of human chorionic gonadotropin (hCG) should be withheld during the current course of treatment to minimize the risk of development of ovarian hyperstimulation syndrome (OHSS).1 Because of the risk of hemoperitoneum resulting from ruptured ovarian cysts, sexual intercourse should be prohibited in patients with substantial ovarian enlargement.1
Ovarian Hyperstimulation Syndrome
OHSS is a condition distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event.1, 8 OHSS is characterized by an apparent dramatic increase in vascular permeability that may result in rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium.1, 8, 25, 26 Early manifestations of OHSS may include severe pelvic pain, nausea, vomiting, and weight gain.1, 8, 25, 26 Other manifestations of OHSS may include abdominal pain/distention, diarrhea, severe ovarian enlargement, dyspnea, and oliguria.1, 8, 25, 26 Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute pulmonary distress, and thromboembolic events.1, 8, 25, 26 Transient liver function test abnormalities, which may be accompanied by morphologic changes (as detected by liver biopsy), also have been associated with OHSS.1, 8 In a clinical trial comparing efficacy and safety of menotropins (Menopur®) and follitropin alfa, the number of serious adverse events related to menotropins or follitropin alfa was low and mainly related to OHSS (event rate 7 or 5%, respectively), which is a predictable outcome in controlled ovarian stimulation procedures.2
Independent risk factors for developing OHSS include young age, low body weight, PCOS, higher doses of exogenous gonadotropins, previous episodes of OHSS, and elevated serum estradiol concentrations.8, 13, 25, 26 OHSS occurs most often after completion of gonadotropin treatment and can develop rapidly, reaching maximum severity after 7-10 days.1, 8 Therefore, patients should be carefully monitored for at least 2 weeks after administration of hCG.1 OHSS usually resolves spontaneously with the onset of menses.1, 8 OHSS is more common, more severe, and more protracted if pregnancy occurs.1
If serious OHSS occurs, gonadotropins, including hCG, should be withheld and hospitalization of the patient should be considered.1, 8 Treatment of OHSS is primarily symptomatic (e.g., bed rest, fluid and electrolyte management, analgesics); diuretics should be avoided except in the late phase of OHSS resolution.1, 26 Pelvic examination or sexual intercourse may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should be avoided.1, 8 If bleeding requiring surgical intervention occurs, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible.1 A clinician experienced in the management of OHSS or fluid and electrolyte imbalances should be consulted.1
The management of OHSS may be divided into 3 phases which include acute, chronic, and resolution phases.1 During the acute phase, therapy should be directed towards preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage.1, 25 Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocadiogram to monitor for hyperkalemia, and abdominal girth should be assessed at least daily.1, 8, 26 Limited IV fluids, electrolytes, and human serum albumin can be used to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume;1, 8 full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation.1 After the acute phase of OHSS has been successfully managed, excessive third space fluid accumulation should be minimized by instituting severe potassium, sodium, and fluid restrictions.1 During the resolution phase, as third space fluid returns to the intravascular compartment, a decrease in hematocrit and increase in urinary output are observed in the absence of any increased intake.1, 25 Peripheral and/or pulmonary edema may occur if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized.1 Diuretics may be indicated to treat pulmonary edema during OHSS resolution.1 Ascitic, pleural, and pericardial fluid should not be removed unless the removal is needed to relieve symptoms such as pulmonary distress or cardiac tamponade.1
Thromboembolic events both in association with and separate from OHSS have been reported in women treated with gonadotropins.1, 14 Intravascular thrombosis and embolism may be venous or arterial in nature and can result in reduced blood flow to vital organs or the extremities.1 Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins.1 Such thromboembolic events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, stroke, and arterial occlusion resulting in loss of limb and, rarely, myocardial infarction (MI).1 In women with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology (ART) need to be weighed against the risks.1 Pregnancy is also associated with an increased risk of thrombosis.1 In rare cases, thromboembolic events have been fatal.1
Serious pulmonary conditions (e.g., atelactasis, acute respiratory distress syndrome, exacerbation of asthma) have been reported in women treated with gonadotropins.1, 14 In rare cases, pulmonary complications have been fatal.1
Ovarian torsion has been reported after treatment with gonadotropins.1 This complication may be related to OHSS, pregnancy, previous abdominal surgery, history of ovarian torsion, previous or current ovarian cyst, and polycystic ovaries.1 Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.1
Multifetal gestations and births have been reported with all gonadotropins, including menotropins.1, 14 Before initiating treatment with menotropins, the woman and her partner should be advised of the potential risk of multifetal gestations and births.1
The incidence of congenital malformations after ART (e.g., in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI]) may be slightly higher than after spontaneous conception.1 However, there are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations.1 This higher incidence may be related to differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics) and to the higher incidence of multifetal gestations after IVF or ICSI.1
Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased.1, 27 Early confirmation of intrauterine pregnancy should be determined by β-hCG testing and transvaginal ultrasound.1
The risk of spontaneous abortion (miscarriage) is increased with gonadotropin treatment; however, causality has not been established.1, 28 The increased risk may be a factor of the underlying infertility.1
There have been infrequent reports of benign and malignant ovarian neoplasms in women who have received multiple-drug treatment for controlled ovarian stimulation; however, a causal relationship has not been established.1
Category X.1, 14 (See Users Guide.)
Menotropins may cause fetal harm when administered to a pregnant woman.1 Menotropins is contraindicated in pregnant women.1 (See Contraindications.)
It is not known whether menotropins is distributed into human milk.1 Because of the potential for serious adverse reactions to menotropins in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy not established.1 Not indicated for use in pediatric patients.1, 7
Not indicated for use in geriatric patients.7
Safety and efficacy not established.1
Safety and efficacy not established.1
Adverse effects reported in at least 2% of women (occurring on or after gonadotropin-releasing hormone [GnRH] administration) undergoing IVF and ICSI receiving menotropins subcutaneously include abdominal pain,1, 2 headache,1, 2 OHSS,1, 2 injection site pain and reaction,1, 2 abdominal cramps,1 abdominal enlargement,1, 2 and injection site inflammation.1, 2
Menotropins is a preparation of gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) extracted from the urine of postmenopausal women) that has undergone additional steps for purification (e.g., hormone adsorption and elution, anion and cation exchange, hydrophobic cation exchange).1, 3, 4, 10 Batch-to-batch consistency is guaranteed by FSH and LH bioactivity testing.1, 2 FSH and LH are both acidic glycoproteins composed of α and β subunits.1, 15 Human chorionic gonadotropin (hCG) is also detected in menotropins and contributes to the LH activity.1, 14, 15 Other urinary proteins are also present as impurities; however, the Menopur® preparation is approximately 25-fold more purified than traditional menotropin preparations, which are no longer commercially available in the US.15
FSH and LH are synthesized and secreted in the lateral portion of the anterior pituitary gland, which is responsive to the pulsatile stimulation of the hypothalamic hormone gonadotropin-releasing hormone (GnRH).4, 18 The development of human ovarian follicles is dependent upon the sequential effects of FSH and LH.4, 17 FSH acts on early antral follicles to stimulate growth, steroidogenesis, and the expression of LH receptors.4, 17 LH in synergy with FSH subsequently acts on the FSH-stimulated follicle to maintain growth and is eventually responsible for the process of luteinization and ovulation.4, 17 Administration of menotropins for 7-20 days produces ovarian follicular growth and maturation in women who do not have primary ovarian failure.1 Treatment with menotropins in most instances results only in follicular growth and maturation; to induce ovulation, a single dose of hCG, which has LH activity, must be given following administration of menotropins when clinical assessment of the patient indicates that sufficient follicular maturation has occurred (e.g., as determined by ultrasound monitoring and serum estradiol concentrations).1, 2, 5
The subcutaneous route of administration of menotropins appears to result in greater bioavailability (as determined by area under the concentration-time curve [AUC] of FSH) than does IM administration.1 After subcutaneous or IM administration of a single 225-unit dose of menotropins, mean peak plasma FSH concentrations are reached at 17.9 or 27.5 hours, respectively.1 Data are lacking on the distribution and metabolism of FSH and LH in humans.1 After multiple-dose subcutaneous or IM administration of menotropins (225 units once, followed by 150 units daily for 6 days), the elimination half-life of FSH averages 11-13 hours.1 Data are lacking on the pharmacokinetics of menotropins in women with renal or hepatic insufficiency.1
Importance of instructing patients to read the manufacturer's patient information and instructions for use.1, 29
Importance of patient informing clinician prior to beginning menotropins treatment about a personal or family history of thrombosis or history of ovarian torsion or ovarian cyst.1, 29
Importance of instructing patients on the correct use and dosage of menotropins.1, 29 Advise patients not to change the dosage or schedule of administration unless told to do so by a clinician.1, 29
Importance of advising patients that if a dose is missed, the next dose should not be doubled; the clinician should be contacted to provide further dosing instructions.1, 29
Importance of patient understanding and following instructions regarding reconstitution of menotropins, duration of treatment, and required monitoring procedures.1, 29
Importance of informing patient of potential adverse effects (e.g., ovarian hyperstimulation syndrome [OHSS]).1, 29 Advise patients of the risk of OHSS-associated symptoms, including pulmonary and vascular complications and ovarian torsion.1, 29
Importance of informing patient regarding the risk of multifetal gestation and birth with the use of menotropins treatment.1, 29
Importance of patients informing a clinician if severe stomach or pelvic pain, stomach bloating, nausea, vomiting, diarrhea, difficulty breathing, decreased or absent urination, or sudden weight gain occurs.1, 29
Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1, 29
Importance of informing patient of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide.). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Ferring. Menopur® (menotropins for injection) for subcutaneous use prescribing information. Parsippany, NJ; 2018 May.
2. European and Israeli Study Group on Highly Purified Menotropin versus Recombinant Follicle-Stimulating Hormone. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril . 2002; 78:520-8. [PubMed 12215327]
3. Practice Committee of American Society for Reproductive Medicine, Birmingham, Alabama. Gonadotropin preparations: past, present, and future perspectives. Fertil Steril . 2008; 90(5 Suppl):S13-20. [PubMed 19007609]
4. Moultry AM, Eaton A, Che S.. A pharmacotherapeutic review of treatment options for infertility in women. Formulary . 2005; 40(10):329-41.
5. National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. London, UK: Royal College of General Practitioners; 2013. [PubMed 25340218]
6. Shrestha D, La X, Feng HL. Comparison of different stimulation protocols used in in vitro fertilization: a review. Ann Transl Med . 2015; 3:137. [PubMed 26207230]
7. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 21-663: Medical review(s). From FDA website. [Web]
8. Practice Committee of American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril . 2008; 90(5 Suppl):S188-93. [PubMed 19007627]
9. Scobey MJ, Raike E, Marshall DC. Mixed protocols: multiple ratios of FSH and LH bioactivity using highly purified, human-derived FSH (BRAVELLE) and highly purified hMG (MENOPUR) are unaltered by mixing together in the same syringe. Reprod Biol Endocrinol . 2005; 3:61. [PubMed 16280072]
10. Ezcurra D, Humaidan P. A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology. Reprod Biol Endocrinol . 2014; 12:95. [PubMed 25280580]
11. Levi Setti PE, Alviggi C, Colombo GL et al. Human recombinant follicle stimulating hormone (rFSH) compared to urinary human menopausal gonadotropin (HMG) for ovarian stimulation in assisted reproduction: a literature review and cost evaluation. J Endocrinol Invest . 2015; 38:497-503. [PubMed 25480425]
12. Revelli A, Pettinau G, Basso G et al. Controlled Ovarian Stimulation with recombinant-FSH plus recombinant-LH vs. human Menopausal Gonadotropin based on the number of retrieved oocytes: results from a routine clinical practice in a real-life population. Reprod Biol Endocrinol . 2015; 13:77. [PubMed 26209525]
13. Polat M, Bozdag G, Yarali H. Best protocol for controlled ovarian hyperstimulation in assisted reproductive technologies: fact or opinion?. Semin Reprod Med . 2014; 32:262-71. [PubMed 24919025]
14. Smith C, Grimm M, Schwegel M. Treatment of infertility in women. J Am Pharm Assoc (2003) . 2012 Jul-Aug; 52:e27-42. [PubMed 22825239]
15. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 21-663: Chemistry review(s). From FDA website. [Web]
16. Doody KJ, Schnell VL, Foulk RA et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril . 2009; 91:1012-7. [PubMed 18371963]
17. Andersen CY, Ezcurra D. Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins. Reprod Biol Endocrinol . 2014; 12:128. [PubMed 25543693]
18. Palermo R. Differential actions of FSH and LH during folliculogenesis. Reprod Biomed Online . 2007; 15:326-37. [PubMed 17854533]
19. Al-Inany H, Aboulghar MA, Mansour RT et al. Ovulation induction in the new millennium: recombinant follicle-stimulating hormone versus human menopausal gonadotropin. Gynecol Endocrinol . 2005; 20:161-9. [PubMed 16019356]
20. Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod . 2006; 21:3217-27. [PubMed 16873892]
21. Bosch E, Vidal C, Labarta E et al. Highly purified hMG versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists--a randomized study. Hum Reprod . 2008; 23:2346-51. [PubMed 18583332]
22. Requena A, Landeras JL, Martínez-Navarro L et al. Could the addition of hp-hMG and GnRH antagonists modulate the response in IVF-ICSI cycles?. Hum Fertil (Camb) . 2010; 13:41-51. [PubMed 20384441]
23. Ferring. Bravelle® (urofollitropin) for injection prescribing information. Parsippany, NJ; 2014 Feb.
24. Ferring. Repronex ® (menotropins) for injection prescribing information. Parsippany, NJ; 2012 Sep.
25. Kumar P, Sait SF, Sharma A et al. Ovarian hyperstimulation syndrome. J Hum Reprod Sci . 2011; 4:70-5. [PubMed 22065820]
26. Prakash A, Mathur R. Ovarian hyperstimulation syndrome. The Obstetrician & Gynecologist. 2013;15:31-5.
27. Schippert C, Soergel P, Staboulidou I et al. The risk of ectopic pregnancy following tubal reconstructive microsurgery and assisted reproductive technology procedures. Arch Gynecol Obstet . 2012; 285:863-71. [PubMed 21947340]
28. Pal L, Jindal S, Witt BR et al. Less is more: increased gonadotropin use for ovarian stimulation adversely influences clinical pregnancy and live birth after in vitro fertilization. Fertil Steril . 2008; 89:1694-701. [PubMed 18440515]
29. Ferring. Menopur® (menotropins for injection) for subcutaneous use, patient instructions for use. Parsippany, NJ; 2018 May.