Indication - Endocrine disorders
Luteinizing hormone (LH)
First added in 2020
Aid to diagnosis
To aid in the diagnosis of anovulation, gonadal dysfunction, precocious puberty, and primary and secondary amenorrhoea; To aid in the evaluation and management of infertility36
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 5B3Z
Summary of evidence evaluation
The LH test is proposed to aid in the diagnoses of various diseases, including DSDs and PCOS, to evaluate the causes of infertility, amenorrhoea and/or irregular menstrual bleeding and suspected Leydig cell insufficiency. Although guidelines and expert opinions state that LH tests are necessary to diagnose these conditions, there is very limited evidence on their diagnostic accuracy and no evidence on their clinical utility on their own. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3
Summary of SAGE IVD deliberations
The consequences of infertility from a personal and social point of view can be dramatic. Fertility is considered a major public health issue by WHO. And testing LH levels is part of several international guidelines and best practice for a large number of indications in fertility medicine, gonadal disorders, anovulation, amenorrhoea and menstrual irregularities. One of the medicines that is routinely used in fertility – clomiphene – is also included in the complementary list of the EML. There is, however, potential for overuse of the test. And there is little evidence available to review for the clinical impact of LH testing. SAGE IVD emphasized that LH testing goes hand in hand with FSH testing; and that result interpretation requires appropriate laboratory infrastructure and the availability of fertility or endocrinology specialists. The group also highlighted the importance of timing in sample collection (although timing requirements may vary depending on the condition being monitored). SAGE IVD noted that the specimen types listed in the LH submission to the EDL did not include urine, even though urine LH is often used in practice, appears in at least one international guideline and is the subject of a published Cochrane review. The group further noted that while LH testing is critical to evaluate and manage infertility, additional investigations may be needed for a definitive diagnosis.
SAGE IVD recommendation
SAGE IVD recommended including the Luteinizing Hormone (LH) test category in the third EDL: • as a disease-specific IVD for use in clinical laboratories (EDL 3, Section II.b, within a new subsection for endocrine disorders); • using an immunoassay format; • to aid in the diagnosis of primary and secondary amenorrhoea, anovulation, gonadal dysfunction and precocious puberty; and • to aid in the evaluation and management of infertility. The group requested the addition of a note to the test category entry in the EDL stating that it is only recommended for use in specialized health care settings. The group further requested that the original submitter of the LH test category be asked to provide information on the applications of LH in urine to support an edit of the EDL entry next year.
Details of submission from 2020
Disease condition and impact on patients LH is a polypeptide hormone produced by the anterior pituitary gland. It induces ovulation and the secretion of progesterone in women and stimulates the production of testosterone in men. LH works synergistically with FSH. The measurement of LH levels, often alongside FSH, is used to aid in the diagnosis of DSDs – for example Turner and Klinefelter syndromes, and PCOS – and to evaluate the causes of infertility, amenorrhoea and irregular menstrual bleeding, and suspected Leydig cell insufficiency (1). DSDs include hypergonadotropic hypogonadism, which is most commonly caused by Turner syndrome in females and Klinefelter syndrome in males. Children with hypogonadism experience delayed puberty if left untreated. Timely diagnosis of hypogonadism allows treatment with prepubertal hormone (sex steroid) replacement (2). For girls, administering estrogen allows secondary sex characteristics to emerge as well as adequate breast and uterine development. Early treatment with human growth hormone may also significantly increase height. For boys, testosterone administration is used to induce puberty (2). Measuring LH after stimulation with GnRH can also aid in the diagnosis of suspected PP (3). PP is defined as the onset of puberty before 8 years of age in girls and 9 years of age in boys (4). The psychosocial and physical burdens of undiagnosed and untreated delayed or precocious puberty are significant, and it is important that all tools to aid in a timely diagnosis be available. PCOS is a complex disorder characterized by chronic anovulation. Common symptoms include irregular menstrual cycle, polycystic ovaries and hirsutism; less common symptoms include infertility, insulin resistance, impaired glucose tolerance (type 2 diabetes) and dyslipidaemia (5). Multiple diagnostic criteria have been adopted for PCOS, but the common denominator appears to be oligoovulation and androgen excess. Infertility diagnostics and management use LH levels to document ovulation. Recent progress in urinary LH testing, which allows qualitative measurement on specimens applied to paper and various materials, has supplanted serum LH as a useful tool (6). Quantitative serum LH levels may, however, still be used to guide management decisions during IVF (7). In males, LH levels are used to evaluate azoospermia (8). Menstrual disorder diagnosis can use LH levels to evaluate irregular menstrual bleeding, particularly oligomenorrhoea and amenorrhoea, by helping to distinguish ovulatory dysfunction from uterine abnormalities as the cause. The use of qualitative urinary LH measurement to evaluate ovulation often now replaces serum levels. Does the test meet a medical need? DSDs. LH levels, often with FSH, are used to distinguish between primary gonadal failure (hypergonadotropic hypogonadism) and deficient gonadal stimulation (hypogonadotropic hypogonadism) (9). Early diagnosis of hypogonadal syndromes allows timely evaluation of the associated anomalies. Administration of growth hormone to young girls in childhood and hormone replacement at puberty for both girls and boys can reduce morbidity and mortality, as well as improve the quality of life (2). LH levels are also used in diagnosing PP. In gonadotropin-dependent PP, elevated LH levels rule out adrenal hyperplasia or CNS lesions (10). In gonadotropin-independent PP, investigating the source of exogenous estrogens can lead to a more timely diagnosis of gonadal hormone-producing cysts or tumours. Early diagnosis of DSDs can reduce morbidity and mortality and improve physical and psychological well-being. Failure to diagnose and treat these conditions, particularly in LMICs, can have a negative economic impact on families where children who are essential to their parents’ survival must be economically independent, meaning that they are employable and able to marry (11). Despite the importance of addressing DSDs, there is considerable variation in how these disorders are managed in HICs and LMICs (11). PCOS. LH results facilitate the diagnosis and treatment of PCOS with the short-term benefit of restoring ovulation and HPO balance (12). Appropriate diagnosis of PCOS allows hormonal treatments that can regulate menstrual cycles, induce ovulation when indicated, decrease androgenic effects and also reduce the risks of metabolic abnormalities that frequently occur with PCOS (5). Equally important are the preventative long-term benefits of reducing the risk of developing diabetes and the metabolic syndrome (5). With the alarmingly rapid increase in obesity and diabetes in LMICs (13), rigorous attempts to diagnose and treat PCOS will have a significant positive impact on public health. Menstrual disorders. Anovulatory or dysfunctional uterine bleeding can impact women’s health and well-being by causing unscheduled and often excessive bleeding. Measuring LH levels is part of the laboratory investigation needed to arrive at the diagnosis. Once the diagnosis is established, bleeding can be controlled by administering appropriate hormonal therapy and carries a high degree of success. Morbidity is decreased by reducing the risk of anaemia due to blood loss and endometrial hyperplasia from estrogen overstimulation (5). Appropriate hormonal replacement also helps prevent the sequelae of estrogen deficiency. Economic impact is also lessened by reducing absences from work or school; social isolation, often directed at menstruating women in LMICs, is avoided too. Infertility. LH levels are important in evaluating male infertility due to azoospermia. The public health impact of addressing this cause of infertility is essential for preserving the nuclear family, but may be particularly important in those countries with a patriarchal culture. How the test is used DSDs. When a diagnosis of hypogonadism is suspected based on history, physical exam and basal gonadotropin levels, exogenous administration of GnRH is often used to differentiate primary gonadal failure (hypergonadotropic) from deficient gonadal stimulation (hypogonadotropic hypogonadism) (9). LH levels will be totally or partially absent in hypogonadotropic cases but will gradually appear in hypergonadotropic ones. Measuring LH after GnRH stimulation can also help diagnose suspected PP (3). An increase in LH levels in response to a GnRH challenge is indicative of central PP (gonadotropic dependent), while no increase supports a diagnosis of peripheral (gonadotropic independent) PP. Early diagnosis of central PP allows for treatment with GnRH agonists that can delay the onset of puberty until a more appropriate age. PCOS. An elevated ratio of LH to FSH (greater than 3) is often used with history and physical exam to support a diagnosis of PCOS (12). Infertility. Elevated LH levels can indicate decreased ovarian function and consequent anovulation. If detected during an infertility workup, elevated LH levels could further suggest a diagnosis of PCOS and prompt confirmation of the presence of polycystic ovaries by ultrasound exam (14). Measuring LH levels may play a more significant role in evaluating male infertility by determining the etiology of azoospermia; low levels indicate a central dysfunction, while elevated levels are indicative of gonadal failure (14). Menstrual disorders. Irregular menses, particularly amenorrhoea and oligomenorrhoea, are generally indicative of a defect at some point in the HPO axis, and LH levels can be used to evaluate the cause. Elevated LH levels indicate ovarian dysfunction or failure, while normal or low levels suggest pituitary or hypothalamic failure (15).
Public health relevance
Prevalence and socioeconomic impact DSDs. Turner syndrome has an incidence of 1 per 2500 live births (2). Klinefelter syndrome has an incidence of 1 per 1000 live births (16). HH is rarer. The incidence of PP is estimated at 1 per 5000–10 000 population. Gonadotropin-independent PP is about five times less common than gonadotropin-dependent PP (17). PCOS. PCOS is thought to be the most common endocrine disorder found in women of reproductive age and impacts all races and ethnicities. In unspecified populations, PCOS has a reported incidence rate of 3–10% (18), although more precise incidence is unknown due to underdiagnosis. Infertility. Estimates suggest that between up to 186 million women globally are infertile (8, 16). Although differing methods and definitions have been used to derive infertility burden, a recent review estimated global prevalence of infertility to be 9% (19). Data on worldwide prevalence of childlessness further estimate that as many as 70 million couples would benefit from medical intervention to achieve pregnancy (20). There are not enough data to assess global infertility prevalence trends over the past 20 years. But these trends can be impacted by a rise in STIs with subsequent impaired reproductive organ function, lifestyle changes and delayed childbearing (8, 16, 19). The economic and social impact of infertility is significant, particularly for women, who often suffer from social isolation, discrimination, disinheritance, depression, abuse, divorce and possible abandonment in old age. Infertility as a common cause of childlessness can also have a broader negative economic impact on families, particularly in LMICs, where children contribute to family incomes and older parents depend on their children for support. Infertility is recognized as an essential component of reproductive health by the UN Programme of Action of the International Conference on Population and Development (21). Paradoxically, nations with the highest overall fertility are also the ones with the greatest prevalence of infertility; these often include LMICs. Given the economic, resource, cultural and religious constraints, infertility services among countries vary significantly. Assays that measure serum LH levels are, however, relatively non-invasive (requiring only a blood draw or finger stick), inexpensive and accessible from laboratories throughout the world. Menstrual disorders. Estimates of the prevalence of menstrual disorders range from 5% to 36% (22); occurrence depends on age, nutritional status and country of residence.
WHO or other clinical guidelines relevant to the test
A 2016 Endocrine Society clinical practice guideline on hormonal replacement in hypopituitarism in adults (9) recommends measuring serum estradiol, FSH and LH in females with oligomenorrhoea or amenorrhoea; and serum T, FSH and LH in males with suspected hypogonadism. In 2003, the Rotterdam European Society of Human Reproduction and Embryology (ESHRE)/ASRM-Sponsored PCOS Consensus Workshop Group published a revised consensus on diagnostic criteria and long-term health risks related to PCOS (23). It states that “serum LH levels should not be considered necessary for the clinical diagnosis of PCOS. LH levels could be useful as a secondary parameter (especially in lean women with amenorrhea or in research)”. In 2018, ACOG (24) identified gonadotropin measures to determine the cause of amenorrhoea as an optional test to consider. A 2013 Endocrine Society clinical practice guideline on the diagnosis and treatment of POCs (25) lists serum LH and FSH in a table of diagnoses to consider for excluding hypothalamic amenorrhoea in select women, depending on presentation.
Evidence for diagnostic accuracy
A 2012 review by Harrington and Palmert (26) identified a total of 19 studies published in English over the past 30 years whose primary objective was to assess the sensitivity of a diagnostic test in differentiating HH from constitutional delay of growth and puberty (CDGP) in adolescents. Although some studies reviewed confirmed the utility of basal LH in discriminating between complete HH and CDPG, consistent results were not observed due perhaps to assay variability. In administering stimulation testing, LH levels following GnRH agonists provided better discrimination. A single inhibin B level was also investigated and showed better predictive value in some studies. In conclusion, basal and stimulated LH levels have limited utility in distinguishing HH from CDPG. Inhibin B may provide better results, but further investigation is needed. A second review by Kalia et al. (27) describes and compares various assay methods used in serum LH measurement in varied clinical conditions. The authors review different methodologies with benefits and limitations, emphasizing reproducibility and sensitivity. Houk et al. (28) evaluated a single basal LH measurement using a commercially available assay and reported a sensitivity of 93% and specificity of 100% for diagnosing central PP. Resende et al. (29) measured basal and GnRH-stimulated LH levels of 315 prepubertal and pubertal children with an immunochemiluminometric assay. Basal LH levels were able to differentiate pubertal from prepubertal stage in boys; in girls, GnRH-stimulated levels were needed to diagnose maturity of the HPG axis.
Evidence for clinical usefulness and impact
Dunkel et al. (30) describe various etiologies, and methods for timely diagnosis, of delayed puberty. When the diagnosis is confirmed, the management to induce puberty is also reviewed in detail. Dwyer et al. (31) discuss the psychological impact of hypogonadism, the treatment and the transition to adulthood. Chen et al. (32) review diagnosis and management of precocious puberty, with treatment outcomes. DSDs. A study by Linglart et al. (33) looked at 64 young girls with Turner syndrome who were treated with recombinant growth hormone. After 4 years a gain in mean height was observed compared with a decrease in mean height in the control group. The authors concluded that early treatment with growth hormone helps to prevent natural evolution towards short stature in most girls with Turner syndrome. This emphasizes the importance of early diagnosis. Lee et al. (34) looked at 76 girls with PP who were treated with leuprolide acetate, a GnRH agonist, every 3 months. At 6 months, 98% exhibited LH suppression and 100% had estradiol suppression. The authors concluded that treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, again demonstrating the clinical importance of a clear diagnosis of PP. PCOS. A study by Nestler et al. (35) looked at the effects of metformin on spontaneous and clomiphene-induced ovulation in PCOS. To restore ovulatory function, women with PCOS were given clomiphene plus metformin vs clomiphene alone. Overall, 89% of women who received metformin had spontaneous ovulation compared with 12% with clomiphene alone. The authors concluded that the ovulatory response to clomiphene can be increased in women with PCOS by decreasing insulin secretion with metformin. Menstrual disorders. The clinical community generally accepts that hormonal therapy is highly successful in treating dysfunctional uterine bleeding. Hurskainen et al. (36) followed more than 200 women with dysfunctional uterine bleeding who were treated with a triphasic preparation of norgestimate and ethinyl E2. More than 80% had documented improvement in bleeding, and this was significantly increased over the placebo group. The conclusion was that the triphasic combination of norgestimate and ethinyl E2 is an effective treatment for metrorrhagic, menometrorrhagic, oligomenorrhagic, and polymenorrheic dysfunctional uterine bleeding.
Evidence for economic impact and/or cost–effectiveness
The cost (in US dollars) of an LH test in the USA is around US$ 23, compared with US$ 4–10 in India, US$ 22 in Australia and US$ 34 in Uganda. Prices among manufacturers are competitive and are not likely to differ significantly. DSDs. LH measures are only somewhat successful in discriminating between HH and CDPG, while inhibin B had better predictive value. But inhibin B may not be available in LMICs and where available, the cost will be higher than an LH test. Measuring LH levels for suspected DSDs, in addition to physical exam and medical history, is a cost-effective step towards diagnosis and management. Menstrual disorders. An LH measurement is a relatively inexpensive test that can determine whether anovulation has occurred, particularly in cases of amenorrhoea. Given the significant syndromes and health issues that are associated with anovulation, such as DSDs or PCOS, there should be no question that confirming anovulation and reducing its morbidity would be cost-effective. Identifying anovulatory women also allows preventative measures to be taken, for example to address estrogen deficiency or the metabolic sequelae of untreated chronic anovulation. The International Osteoporosis Foundation estimates the cost of osteoporotic fractures, which are increased in the hypoestrogen state, at €37 billion every year in the European Union, and US$ 19 billion each year in the USA. Estimates of the cost of diabetes and metabolic syndrome are less definable, but identifying those at risk and taking preventative measures should offset the cost of measuring reproductive hormone levels when the diagnosis is suspected.
Ethical issues, equity and human rights issues
LH measurement plays a significant part in the diagnosis of DSDs attributable to hypogonadism, and identifying these disorders is essential to prevent further illness, death and economic impact. But it is just as important to ensure that the resources needed to replace deficient hormones or to treat the disease are available, even in LMICs, to decrease overall morbidity. Identifying PP should similarly carry with it an obligation to provide treatment that delays puberty. LH levels are also used to diagnose and manage infertility, particularly as it relates to assisted reproductive technology. But infertility may not be assigned a high priority in LMIC health care systems. To address this issue, WHO recommended in 2001 that infertility be viewed as a world health problem and encouraged the development of lower-cost assisted reproductive technology. Progress towards this end needs to be accelerated before the full potential of LH as an infertility diagnostic test can be appreciated. Measurement of LH levels should be accessible to most global populations. Its use will reduce inequalities in health care, provided that systems delivering health care are both equipped and prepared to follow through and make available the treatments that are indicated by the results.
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