Publication Details



The gonadotropins are peptide hormones that regulate ovarian and testicular function and are essential for normal growth, sexual development and reproduction. The human gonadotropins include follicle stimulating hormone (FSH) and luteinizing hormone (LH) which are made in the pituitary, and chorionic gonadotropin (hCG) which is made by the placenta. All three gonadotropins are heterodimeric proteins that consist of two peptide chains, the alpha chain is similar in all three, whereas the beta chain is unique and determines the fine receptor specificity and function of each hormone. The pituitary gonadotropins are under the control of gonadotropin releasing hormone (GnRH), a decapeptide produced in the hypothalamus and released in response to circulating levels of estrogens and progesterone. Highly purified and recombinant formulations of the gonadotropins have been developed and used in the treatment of hypogonadism and infertility. Synthetic forms of GnRH have been used with the gonadotropins in assisted reproductive techniques and in vitro fertilization. Therapeutic use of the gonadotropins and GnRH has not been linked to serum enzyme elevations or with clinically apparent liver injury. However, in high doses, the gonadotropins can induce the ovarian hyperstimulation syndrome (OHSS) which may be accompanied by liver test abnormalities, jaundice, edema and ascites.

Follicle stimulating hormone (FSH) is a pituitary hormone that regulates growth, sexual development and reproduction, including menstruation, follicular development and ovulation. FSH is regulated, at least in part, by GnRH produced in the hypothalamus in response to multiple signals including circulating levels of sex hormones. FSH interacts with receptors on ovarian follicles and is the major survival factor for the maturing follicles. A surge in FSH levels occurs in the middle of the menstrual cycle leading to ovulation. In men, FSH promotes spermatogenesis and androgen responsiveness in the testes. Thus, FSH is essential for sexual maturation and reproduction in both men and women. Partially and highly purified urinary derived FSH (menotropins, Menopur which also has LH activity; urofollitropin, Bravelle) and recombinant forms of FSH (follitropin alpha, Follistim, Gonal F) are available and approved for use in treatment of infertility and hypogonadism. They are generally given by subcutaneous injection daily or several times weekly. The dose and appropriate regimen vary by indication. These agents should be used only by health care workers with expertise in management of infertility and hypogonadism.

Luteinizing hormone (LH) is a pituitary hormone that is essential for sexual development and reproduction in both men and women. LH is regulated by GnRH from the hypothalamus which is sensitive to circulating levels of sex hormones. LH interacts with receptors on ovarian follicles and promotes their maturation. In the middle of the menstrual cycle, a surge of LH triggers ovulation and production of progesterone by the corpus luteum that is necessary for the maturation of the uterine endometrium for implantation of the fertilized egg. In males, LH stimulates production of testosterone by the testes. LH is used clinically in assisted reproduction techniques (ART) and in vitro fertilization (IVF) to stimulate ovarian follicle maturation. Both urinary derived (menotropin, Menopur, which also has FSH activity) and recombinant forms (lutropin alfa: Luveris) of human LH have been developed, but not all are available in the United States. LH is generally administered by subcutaneous injection in a cyclic and step-wise fashion. The dosages and regimens of administration vary by indication. These agents should be used only by health care workers with expertise in management of infertility and hypogonadism.

Human chorionic gonadotropin (kor" ee on' ik) (hCG) is a polypeptide hormone produced by the placenta following implantation of the fertilized egg. Circulating human chorionic gonadotropin interacts with the luteinizing hormone receptors of the ovary, promoting the corpus luteum and its production of progesterone which is necessary to maintain pregnancy and support the growth of the fetus. Injections of hCG mimic the surge in LH that is necessary for ovulation and are used in the therapy of female infertility, in assisted reproduction techniques. In clinical trials, hCG resulted in pregnancies in approximately 30% of women. hCG prepared from urine of pregnant women and was approved for use in the United States in 1967 as treatment of ovulatory dysfunction in women desiring pregnancy. Subsequently, recombinant forms of hCG have been developed and licensed for use. Currently, hCG is available as a powder or in solution generically and under trade names such as Novarel and Pregnyl. Recombinant hCG is available as Overle. The dose and regimen of hCG therapy varies by indication and it should be used only by physicians with expertise in the management of infertility and hypogonadism. Common side effects include headache, nausea, anorexia, and local injection reactions. Uncommon, but potentially severe adverse events include ovarian hyperstimulation syndrome.

Gonadotropin releasing hormone (GnRH) is a decapeptide, neurohormone produced in the hypothalamus and released in a pulsatile manner. GnRH acts on the pituitary leading to synthesis and secretion of LH and FSH. GnRH activity is low during childhood and increases markedly during puberty. The proper pulsatile activity of GnRH is necessary for reproduction, but once pregnancy is established it is no longer necessary, gonadotropin activity being assumed by chorionic gonadotropin produced by the placenta. Synthetic GnRH is used as a part of assisted reproductive techniques as a means of controlling ovarian overstimulation. GnRH is available in solution for injection and its use should be restricted to physicians with expertise in assisted reproductive techniques. In addition, several synthetic GnRH analogues and GnRH antagonists have been developed as therapy of various conditions including hormone-sensitive cancers (breast and prostate), endometriosis and precocious puberty. These products are discussed separately in LiverTox as gonadotropin releasing hormone agonists and antagonists.


The gonadotropic hormones are usually given in low doses for a short time only and there is little evidence or reason to suspect that they may be hepatotoxic. Injections of LH, FSH, hCG and GnRH, either in short courses or as single injections in assisted reproductive techniques and to stimulate ovulation, have not been linked convincingly to instances of serum enzyme elevations. Even use of more prolonged courses of the gonadotropins for hypogonadism has also not been associated with serum enzyme elevations or other evidence of liver injury. Furthermore, no instances of idiosyncratic, clinically apparent liver injury have been attributed to use of the gonadotropins, alone or in combination.

When used in women for the treatment of infertility, however, the gonadotropins can lead to the ovarian hyperstimulation syndrome (OHSS), severe forms of which can be accompanied by serum enzyme elevations, jaundice and even ascites. This syndrome typically arises within 4 to 14 days of ovarian stimulation with gonadotropins or clomiphene and is characterized by the onset of abdominal pain and distension with ascites and enlarged ovaries and ovarian cysts. There can be marked fluid shifts with hemoconcentration and rapid onset of severe ascites and pleural effusions. Liver tests are elevated in 25% to 40% of patients with OHSS, typically with mild-to-moderate increases in ALT and AST values, but minimal or no elevations in serum bilirubin and alkaline phosphatase levels. The liver test abnormalities resolve with resolution of the OHSS usually within 2 to 3 weeks of onset. In severe instances, OHSS can be fatal, but death is usually due to dehydration, shock and septicemia rather than hepatic failure. In typical cases with abnormal liver enzymes, liver histology reveals nonspecific changes of sinusoidal dilatation, mild fat accumulation and focal inflammatory infiltrates with macrophages and lymphocytes. OHSS is less common with clomiphene than with human chorionic gonadotropin (hCG) induction of ovulation and appears to be more common with the use of FSH and LH. The liver injury that accompanies OHSS is not due to the gonadotropins per se, but rather secondary to their effects on target organs.

Likelihood score [hCG, FSH, LD, GnRH): E (unlikely causes of clinically apparent liver injury but may precipitate evidence of liver injury as a part of the OHSS).

Mechanism of Injury

A mechanism of injury that might lead to serum enzyme elevations during gonadotropin therapy is not known. The gonadotropins are peptide hormones and are usually metabolized by the cell on which they act. The liver test abnormalities found during OHSS may be due to fluid shifts, hypovolemia and ischemia.

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) during gonadotropin therapy should lead to dose reduction or temporary cessation. The gonadotropins and gonadotropin releasing hormone have not been implicated in cases of severe hepatitis, acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no reason to suspect any degree of cross sensitivity in risk for hepatic injury among the various gonadotropins and other agents used to treat infertility.

Drug Class: Obstetrical and Gynecological Agents, Infertility Agents


Case 1. Jaundice and liver injury during severe ovarian hyperstimulation syndrome.

[Modified from: Obrzut B, Kuczy.ski W, Grygoruk C, Putowski L, Kluz S, Skret A. Liver dysfunction in severe ovarian hyperstimulation syndrome. Gynecol Endocrinol 2005; 21: 45-9. PubMed Citation.]

A 32 year old woman with infertility received a cycle of every other day FSH injections followed by a single infusion of hCG for ovulation induction in preparation for natural insemination and presented several days later with nausea, vomiting, abdominal distention and shortness of breath. On examination, she had tachycardia (110/min) and blood pressure was 100/70 mm Hg. She was pale, diaphoretic and had diffuse tenderness and swelling of the abdomen. Laboratory testing suggested hemoconcentration (hematocrit 51%) and hypoproteinemia (total protein 4.8 g/dL). Ultrasonography demonstrated enlarged ovaries with multilocular cysts (14-18 cm), with mild ascites. She received fluids and albumin infusions, but worsened over the next several days, developed jaundice and worsening ascites (Table). A pleural effusion was present on chest X-ray. She underwent repeated paracenteses and was treated with fluids, antibiotics, corticosteroids and heparin. She gradually improved and was discharged after 7 weeks in the hospital. In follow up, she had an uncomplicated pregnancy and delivered a normal child at 38 weeks gestation.

Key Points

Laboratory Values

* Values estimated from Figure 1, normal values imputed.


The gonadotropins do not seem to be intrinsically hepatotoxic, but they can induce the ovarian hypersensitivity syndrome, severe forms of which may be accompanied by hepatic injury. The pattern of injury is usually a mild jaundice with mild-to-moderate serum enzyme elevations accompanying severe hypoproteinemia and ascites. Recovery usually requires 1 to 4 weeks and follows the resolution of the hyperestrogenism and ovarian hyperstimulation. In this case, there were marked serum aminotransferase elevations with moderate increases in alkaline phosphatase levels, suggesting an element of hypovolemic shock and hepatic ischemic injury. Serial INR, albumin and platelet count results were not provided. The patient ultimately recovered and delivered a "viable" infant after 38 weeks of gestation.



Follicle Stimulating Hormone – Bravelle®

Luteinizing Hormone – Menopur®

Human Chorionic Gonadotropin – Generic, Novarel® Pregnyl®

Gonadotropin Releasing Hormone – Generic


Infertility Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 26 March 2018

Abbreviations: OHSS, ovarian hyperstimulation syndrome; FSH, follicle stimulating hormone; LH, luteinizing hormone; GnRH, gonadotrophin releasing hormone; hCG, human chorionic gonadotrophin.

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    (Among 259 infertile women treated with rFSH for ovarian stimulation received one of 4 doses of rLH or uhCG for final follicular maturation, success rates were similar with all regimens, but OHSS was less in those who received a single dose of rLH compared to multiple doses or urinary hCG).
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    (33 year old woman with infertility developed abdominal distension, ascites and OHSS 11 days after embryo transfer with daily injections of leuprolide and several injections of FSH, hCG and progesterone [ALT 265 U/L, bilirubin and Alk P normal] resolving in 1-2 weeks).
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    (28 year old woman with infertility developed abdominal pain and distension 1 day after embryo transfer [bilirubin 0.6 mg/dL, ALT 462 U/L, Alk P 706 U/L, prothrombin time 19 sec], resolving over the ensuing 3 weeks).
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    (Controlled trial of hCG vs placebo injected twice weekly for 3 months in 40 older men with partial androgen deficiency, found increases in serum testosterone and decreases in LH and FSH, but no improvement in muscle strength or sexual function and slight increase in body weight; no mention of ALT elevations or hepatotoxicity).
  • Dickey RP, Thornton M, Nichols J, Marshall DC, Fein SH, Nardi RV; Bravelle IVF Study Group. Comparison of the efficacy and safety of a highly purified human follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta for in vitro fertilization: a prospective, randomized study. Fertil Steril 2002; 77: 1202-8. [PubMed: 12057729]
    (Controlled trial of recombinant vs urinary FSH injections in 177 women undergoing in vitro fertilization found similar rates of efficacy and side effects with 6 cases of OHSS, one of them severe; no mention of ALT elevations or hepatotoxicity).
  • Bouloux P, Warne DW, Loumaye E; FSH Study Group in Men's Infertility. Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertil Steril 2002; 77: 270-3. [PubMed: 11821082]
    (Among 19 infertile men treated with recombinant FSH injected 3 times weekly for 18 months to stimulate spermatogenesis, side effects were largely due to increase in testosterone levels; no mention of ALT elevations or hepatotoxicity).
  • Delvigne A, Rozenberg S. Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 2003; 9: 77-96. [PubMed: 12638783]
    (Review of OHSS mentions that liver abnormalities occur in 26-40% of cases, typically with elevations in ALT, but normal bilirubin and Alk P values, resolving in all cases with resolution of the syndrome).
  • López E, Gunby J, Daya S, Parrilla JJ, Abad L, Balasch J. Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy. Reprod Biomed Online 2004; 9 (4): 382-90. [PubMed: 15511336]
    (Among 76 women with infertility and polycystic ovarian syndrome treated with 3 cycles of either low dose rFSH or clomiphene to induce follicular development, 2 cases of mild OHSS occurred in the rFSH treated patients and none with clomiphene; other adverse events were not mentioned).
  • Keye WR, Webster B, Dickey R, Somkuti S, Crain J, Scobey MJ. Subcutaneously administered Menopur, a new highly purified human menopausal gonadotropin, causes significantly fewer injection site reactions than Repronex in subjects undergoing in vitro fertilization. Reprod Biol Endocrinol 2005; 3: 62. [PMC free article: PMC1309620] [PubMed: 16280073]
    (Among 125 women with infertility treated with leuprolide and one of two forms of human urinary menopausal gonadotropins for up to 12 days before hCG administration, side effects were with the two products, except for fewer injection site reactions with the more highly purified preparation; no mention of ALT elevations of hepatotoxicity).
  • Abdelmassih V, Oliveira FG, Goncalves SP, Varella AD, Diamond MP, Abdelmassih R. A prospective, randomized and blinded comparison between 10,000 IU urinary and 250 microg recombinant human chorionic gonadotropin for oocyte maturation in in vitro fertilization cycles. J Assist Reprod Genet 2005; 22: 149-53. [PMC free article: PMC3455286] [PubMed: 16021858]
    (Controlled trial of single injections of urinary vs recombinant hCG for oocyte maturation in 100 women with infertility found similar efficacy, but more local injection site reactions with uhCG [38%] than rhCG [13%]; no mention of ALT elevations or hepatotoxicity).
  • Obrzut B, Kuczy.ski W, Grygoruk C, Putowski L, Kluz S, Skret A. Liver dysfunction in severe ovarian hyperstimulation syndrome. Gynecol Endocrinol 2005; 21: 45-9. [PubMed: 16048801]
    (32 year old woman with infertility developed severe OHSS with marked ascites, dyspnea and hypovolemia after therapy with clomiphene and hCG [bilirubin 5 mg/dL, ALT 3372 U/L, Alk P 310 U/L], with full recovery over the ensuing month).
  • Binder H, Dittrich R, Einhaus F, Krieg J, MüA, Strauss R, Beckmann MW, Cupisti S. Update on ovarian hyperstimulation syndrome: Part 1--Incidence and pathogenesis. Int J Fertil Womens Med 2007; 52: 11-26. [PubMed: 17987884]
    (Review of OHSS, which arises in 0.2-1% of stimulation cycles in assisted reproduction and may be mediated by VEGF levels of which correlate with hCG levels; liver enzyme elevations, predominantly ALT and AST, arise in 25-40% of cases possibly due to the increased capillary permeability of OHSS).
  • Kaufmann R, Dunn R, Vaughn T, Hughes G, O'Brien F, Hemsey G, Thomson B, O'Dea LS. Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women. Clin Endocrinol (Oxf) 2007; 67: 563-9. [PubMed: 17692110]
    (Injections of recombinant LH and FSH were given to 31 hypogonadal women in 54 cycles of 9 to 28 days and achieved follicular development in 87%; "There were no clinically significant abnormalities for any of the blood chemistry...parameters assessed").
  • Moon SY, Choi YS, Ku SY, Kim SH, Choi YM, Kang IS, Kim CH. Comparison of the efficacy and safety of a new recombinant human follicle-stimulating hormone (DA-3801) with follitropin-alpha (Gonal-F) in women undergoing controlled ovarian hyperstimulation for assisted reproductive technology. J Obstet Gynaecol Res 2007; 33: 305-15. [PubMed: 17578360]
    (Controlled trial of two formulations of rFSH in 97 women undergoing ovarian stimulation found similar rates of efficacy and side effects; there were minor changes in ALT and Alk P levels, "but these changes were within reference ranges and not clinically significant").
  • Shoham Z, Smith H, Yeko T, O'Brien F, Hemsey G, O'Dea L. Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study. Clin Endocrinol (Oxf) 2008; 69: 471-8. [PubMed: 18485121]
    (Among 39 women with infertility treated with recombinant FSH and either recombinant LH or placebo in an attempt to stimulate follicular development, the addition of rLH provided a higher rate of follicular development, but no difference in rates of adverse events; one placebo recipient had a transient ALT elevation).
  • Drugs for ovulation induction. Med Lett Drugs Ther 2011; 53 (1376): 86-8. [PubMed: 22033212]
    (Concise review of the efficacy and safety of drugs used for ovarian induction mentions that common side effects of FSH, LH and hCG include injection site reactions, headache, abdominal pain and nausea, and that FSH and LH can cause OHSS which can be severe and even fatal; no mention of ALT elevations or hepatotoxicity).
  • Ashrafi M, Kiani K, Ghasemi A, Rastegar F, Nabavi M. The effect of low dose human chorionic gonadotropin on follicular response and oocyte maturation in PCOS patients undergoing IVF cycles: a randomized clinical trial of efficacy and safety. Arch Gynecol Obstet 2011; 284: 1431-8. [PubMed: 21210134]
    (Among 90 women with polycystic ovary syndrome undergoing assisted reproduction treated with FSH and with one of three regimens of hCG to induce ovulation, severe OHSS occurred only in those in whom FSH was continued in full dosage).
  • Checa MA, Espinós JJ, Requena A. Efficacy and safety of human chorionic gonadotropin for follicular phase stimulation in assisted reproduction: a systematic review and meta-analysis. Fertil Steril 2012; 97: 1343-50. e1-3. [PubMed: 22464087]
    (Systematic review of the literature on use of hCG for follicular phase stimulation identified 11 relevant publications; discussion of adverse events was restricted to miscarriage and OHSS, neither of which was more frequent with hCG than with comparator treatments such as FSH and LH).
  • Alviggi C, Cognigni GE, Morgante G, Cometti B, Ranieri A, Strina I, Filicori M, et al. A prospective, randomised, investigator-blind, controlled, clinical study on the clinical efficacy and tolerability of two highly purified hMG preparations administered subcutaneously in women undergoing IVF. Gynecol Endocrinol 2013; 29: 695-9. [PubMed: 23638621]
    (Among 157 women receiving one of two menopausal gonadotropin preparations as a part of assisted reproductive techniques, success rates and adverse event rates were similar, two women developed mild OHSS, no mention of ALT elevations or hepatotoxicity).
  • Figueiredo JB, Nastri CO, Vieira AD, Martins WP. Clomiphene combined with gonadotropins and GnRH antagonist versus conventional controlled ovarian hyperstimulation without clomiphene in women undergoing assisted reproductive techniques: systematic review and meta-analysis. Arch Gynecol Obstet 2013; 287: 779-90. [PubMed: 23250342]
    (Review of 7 studies comparing the safety of regimens to induce ovulation with or without clomiphene mentions that OHSS is less common in regimens that include clomiphene [0.5% vs 4%]).
  • Bellavia M, de Geyter C, Streuli I, Ibecheole V, Birkhäer MH, Cometti BP, de Ziegler D. Randomized controlled trial comparing highly purified(HP-hCG) and recombinant hCG (r-hCG) for triggering ovulation in ART. Gynecol Endocrinol 2013; 29: 93-7. [PubMed: 23116325]
    (Among 147 women receiving either recombinant or highly purified urinary hCG preparations while undergoing assisted reproductive techniques, adverse event rates were similar and 5 women developed moderate-to-severe OHSS; no mention of ALT elevations or hepatotoxicity).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to gonadotropins or arose as a complication of assisted reproductive techniques).
  • Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril 2016; 106: 1634-47. [PubMed: 27678032]
    (Guidelines on management and prevention of OHSS, an uncommon but serious complication of assisted reproductive techniques occuring in 1-5% of cycles, severe instances accompanied by abdominal pain, ascites and liver enzyme elevations; rates are higher with GnRH agonists than antagonists).
  • Humaidan P, Chin W, Rogoff D, D'Hooghe T, Longobardi S, Hubbard J, Schertz J; ESPART Study Investigators. Efficacy and safety of follitropin alfa/lutropin alfa in ART: a randomized controlled trial in poor ovarian responders. Hum Reprod 2017; 32: 544-55. [PMC free article: PMC5850777] [PubMed: 28137754]
    (Among 939 women who had a poor response to ovarian stimulation during assisted reproductive technology [ART] and who underwent repeat ART with either recombinant hFSH alone or its combination with recombinant hLH, rates of oocyte retrieval were similar as were adverse event rates; only one patient developed OHSS which was mild and self-limited).