Disease condition and impact on patients FSH is a polypeptide hormone produced by the anterior pituitary gland and is responsible for stimulating the development of ovarian follicles in women and for supporting testicular Sertoli cells critical for spermatogenesis in males. In both males and females, FSH secretion is regulated by a balance of positive and negative feedback mechanisms involving the hypothalamic-pituitary axis, the reproductive organs, and the pituitary and sex steroid hormones. Measuring FSH levels provides insight into the functioning of the HPG axis and is used in the clinical evaluation of infertility (both female and male), menstrual irregularities, pituitary disorders, precocious or delayed puberty, and ovarian/testicular dysfunction. Diseases caused by malfunction of the HPG axis are varied with wide-ranging impacts; they affect both HICs and LMICs. Infertility. See “Socioeconomic impact”. Ovarian reserve. The number of ovarian follicles present in the ovaries (oocytes) is established at birth and declines with time throughout a woman’s lifetime without regeneration. Menstrual disorders. Irregular menses, particularly amenorrhoea and oligomenorrhoea, generally indicate a defect at some point in the hypothalamic-pituitary-ovarian-uterine axis. Polycystic ovary syndrome (PCOS) causes irregular menstrual cycles, polycystic ovaries and hirsutism (1); it may also include infertility, insulin-resistance, impaired glucose tolerance (type 2 diabetes) and dyslipidaemia (1). It is associated with negative psychosocial impacts, and the premature pubertal growth spurt and accelerated bone maturation can also result in reduced adult height (2). Gonadal dysfunction. Hypergonadotropic hypogonadism is most commonly caused by Turner syndrome in females and Klinefelter syndrome in males. Exogenous administration of GnRH is often used to differentiate primary hypergonadotropic and HH (3). Following administration of exogenous GnRH, FSH levels will be totally or partially absent in HH but will gradually appear in response to the exogenous GnRH in HH. Children with hypogonadism experience delayed puberty if left untreated. Timely diagnosis of hypogonadism allows treatment with prepubertal hormone replacement (4). For girls, administering estrogen allows secondary sex characteristics to emerge and facilitates 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 (4). Does the test meet a medical need? Infertility. FSH levels can help diagnose potential causes of infertility. For example, they may help distinguish a gonadal from a pituitary cause of anovulation or azoospermia; or they may be used to give an indication of ovarian reserve and predict IVF success (5). Although AMH has gained favour for these purposes (6), FSH is a less expensive and more accessible test and so offers a more reasonable choice, especially for LMICs introducing infertility services (including IVF). Ovarian reserve. Ovarian reserve testing can inform women of their reproductive lifespan. Confirming the presence of viable oocytes and the potential to ovulate is also useful for female cancer patients of reproductive age who are being treated with gonadotoxic therapy. Menstrual disorders. FSH levels can be used in the evaluation of irregular menstrual bleeding, particularly oligomenorrhoea and amenorrhoea, by helping to distinguish ovulatory dysfunction from uterine abnormalities as the cause. Confirmation that irregular menstrual bleeding is caused by hypothalamic-pituitary-ovarian (HPO) dysfunction allows corrective treatment with hormonal intervention and carries a high degree of success in regulating cycles. In addition, appropriate hormonal replacement will aid in preventing the sequelae of estrogen deficiency. 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 (8). 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 such as diabetes and metabolic syndrome, which frequently occur with PCOS. Gonadal dysfunction. Gonadal dysfunction can be evaluated by measuring FSH levels to distinguish between primary gonadal failure (hypergonadotropic) and deficient gonadal stimulation (hypogonadotropic hypogonadism) (3). High FSH levels also provide confirmation of hypogonadism in the evaluation of primary amenorrhoea. Early diagnosis of hypogonadal syndromes allows more complete evaluation of associated anomalies. Furthermore, 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 quality of life (4). FSH levels can also aid in the diagnosis of suspected PP (2). In gonadotropin-dependent PP, elevated FSH levels rule out adrenal hyperplasia or CNS lesions (9). In gonadotropin-independent PP, investigating the source of exogenous estrogens can lead to a more timely diagnosis of gonadal hormone-producing cysts or tumours. 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. How the test is used FSH levels are generally used alongside physical exam and other laboratory tests or procedures to confirm a diagnosis. For example, in cases where the physical exam of a child suggests delayed puberty, FSH can help distinguish between a pituitary-hypothalamic disorder and a primary gonadal dysfunction. FSH can be done with other laboratory tests, for example with LH levels to determine the etiology of hypogonadism. The ratio of LH/FSH may also be used to support a diagnosis of PCOS. Infertility. FSH levels are usually included in a basic infertility workup, generally as part of a panel of reproductive markers. Elevated FSH levels can indicate decreased ovarian function, and consequent anovulation and insufficient ovarian reserve. FSH levels measured on menstrual cycle days 2, 3 and 4 can also be used in evaluating whether an IVF cycle will be successful, although the sensitivity for predicting poor response is highly variable and dependent on the cut-off point. The sensitivity for predicting failure to achieve pregnancy is poorer (10). FSH levels may also be useful in predicting diminished ovarian reserve in response to a clomiphene challenge. Studies show that measuring FSH levels after a clomiphene challenge is less specific than basal FSH but results in increasing specificity (11). The knowledge that an IVF cycle is likely to be unsuccessful can save costs and may also help alleviate the disappointment and stress that couples experience when assisted reproduction fails. Ovarian reserve. Other methods, including AMH and antral follicular count, already exist to evaluate ovarian reserve in subfertile women (12), but measuring FSH levels at predetermined times of a menstrual cycle (typically day 3) remains an important test (10). Single FSH measures are not predictive of the perimenopausal state or the timing of menopause, but elevated FSH levels can confirm menopausal status (13), particularly in women who have had hysterectomies (with ovaries intact) and in whom the absence of menses cannot be used as a reliable indicator of ovarian function. Menstrual disorders. FSH levels are used in evaluating the etiology of irregular menstrual bleeding, particularly amenorrhoea and oligomenorrhoea. Elevated FSH levels indicate ovarian dysfunction or failure, while normal or low levels suggest pituitary or hypothalamic failure (14). Multiple diagnostic criteria have been adopted for PCOS, but the common denominator appears to be oligoovulation and androgen excess. Gonadal dysfunction. Measuring FSH after GnRH stimulation can help diagnose suspected PP (15). An increase in FSH levels in response to a GnRH challenge indicates 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.

Prevalence and socioeconomic impact Infertility. Estimates suggest that up to 186 million women globally are infertile (16, 17). Although differing methods and definitions have been used to derive infertility burden, a recent review estimated the global prevalence of infertility to be 9% (18). Data on worldwide prevalence of childlessness further estimate that as many as 70 million couples would benefit from medical intervention to achieve pregnancy (19). 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 sexually transmitted infections (STIs) with subsequent impaired reproductive organ function, lifestyle changes and delayed childbearing (16–18). The economic and social impact of infertility is significant, particularly for women, who will 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 (20). Paradoxically, nations with the highest overall fertility are also the ones with the greatest prevalence of infertility and these often include LMICs. Given the economic, resource, cultural and religious constraints in these countries, infertility services among them vary significantly. Assays that measure serum FSH 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% (21); occurrence depends on age, nutritional status and country of residence. PCOS, which is a subset of menstrual irregularity, is thought to be the most common endocrine disorder found in women of reproductive age (22) and impacts all races and ethnicities. In unspecified populations, PCOS has a reported incidence rate of 3–10%, although more precise incidence is unknown due to underdiagnosis. Gonadal dysfunction. Turner syndrome has an incidence of 1 per 2500 live births (4). Klinefelter syndrome has an incidence of 1 per 1000 live births (1). HH is rarer. The incidence of PP is estimated to be 1 per 5000–10 000 children, and occurs in females at ten times the frequency in males (2). Gonadotropin-independent PP is about five times less common than gonadotropin-dependent PP (2). Early diagnosis of DSDs can reduce deaths and illness and improve physical and psychological well-being. But there is considerable variation in how these disorders are managed in resource-rich and resource-poor countries. Closing the gap requires establishing specialized treatment centres, appropriate diagnostic algorithms, strong laboratory quality assurance and accessible treatments (23).

A 2016 Endocrine Society clinical practice guideline on hormonal replacement in hypopituitarism in adults (3) recommends measuring serum estradiol (E2), FSH and LH in females with oligomenorrhoea or amenorrhoea; and serum T, FSH and LH in males with suspected hypogonadism. In 2014, ACOG (24) listed measuring FSH and estradiol (two random tests at least 1 month apart) when there has been menstrual irregularity for at least three consecutive months as a way of diagnosing and initially evaluating primary ovarian insufficiency. For example, it identifies measuring FSH and estradiol levels to rule out causes of ovarian insufficiency such as pregnancy, thyroid disease and hyperprolactinaemia. It goes on to state that if gonadotropins are elevated into the menopausal range (typically, FSH levels of greater than 30–40 mIU/mL), a repeat FSH measurement should be done a month later; if the FSH is still elevated, a diagnosis of primary ovarian insufficiency can be established. The ASRM (10) Practice Committee acknowledged that high FSH values have been associated with, but do not necessarily predict, both poor ovarian stimulation and the failure to conceive. It stated that “a single FSH value has very limited reliability because of inter- and intra-cycle variability (particularly if it is not elevated). An elevated FSH value has good specificity but may represent a false positive especially when used in a low-risk population. Given the inter-assay variability of FSH, the cut-off point selected by an IVF program ideally should be based on its own data or on data from studies using the same FSH assay”.

A large systematic review (37 studies) published by Broekmans et al. in 2006 (25) evaluated clinical accuracy to predict IVF outcomes. Sensitivity was seen to vary and was highly dependent on FSH cut-off points. Cut-off points less than 10 IU/L had a sensitivity to predicting a poor outcome of 65–100%, with specificity of 5–100%. Positive likelihood ratios for a positive result ranged from 1.1 to 4.4 IU/L. The sensitivity to predicting non-pregnancy at cut-off points less than 10 IU/L was 26–78% with specificity of 27–87%. Positive likelihood ratios for a positive result using these lower cut-off points ranged from 1.1 to 6.8 IU/L. The authors conclude that basal FSH may only be adequate for predicting poor response and non-pregnancy at high cut-off points. Further, it may not be suitable as a diagnostic test to exclude patients from undergoing IVF, but more as a screening test for counselling patients and determining further diagnostic steps. Despite the review’s limited support for the use of basal FSH levels in assisted reproductive procedures, LMICs offering IVF may favour using basal FSH at higher cut-off points as it is accessible and less costly than other diagnostic tools for predicting outcome.

A 2019 review by Mikhael et al. (26) suggests that, in general, basic evaluation of hypothalamic-pituitary failure includes measurement of FSH (with LH and estradiol). Overall management of hypothalamic-pituitary failure depends on patient needs. For example, in young women of reproductive age where FSH levels (with estradiol) are used to diagnose ovarian insufficiency, management can include reassurance and education about other reproductive options. This may also apply to patients with mosaic Turner syndrome who become aware of impending follicular atresia and who wish to preserve fertility through oocyte or embryo cryopreservation. In cases where ovarian failure is confirmed, either premature or due to natural menopause, the diagnosis allows for monitoring the effects of estrogen deficiency and consideration of hormonal replacement to prevent or delay the associated morbidity. Infertility. A 2003 WHO study (27) looked at high singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility. All patients started with clomiphene for ovulation induction; those who did not ovulate within three treatment cycles of incremental daily doses up to 150 mg for five consecutive days or ovulatory CC patients who did not conceive within six cycles underwent gonadotropin induction of ovulation applying a step-down dose regimen. Of 240 consecutive women, there were 134 pregnancies ending in a singleton live birth (56% of women). The cumulative pregnancy rate after 12 and 24 months of follow-up was 50% and 71%, respectively. The study concluded that classical ovulation induction produces very good results in normogonadotrophic anovulatory infertility. Akande et al. (28), looked at using FSH to assess the risk of IVF treatment cancellation due to poor ovarian response in 536 women undergoing IVF. Modelling showed that high FSH and age were independent predictors of poor response to hyperstimulation and were independently associated with the risk of treatment cancellation. In 2000, Creus et al. (29) looked at day 3 serum inhibin B, FSH and age as predictors of assisted reproduction treatment outcome. They studied 120 women undergoing assisted reproductive technology, including 40 consecutive cycles cancelled due to poor follicular response. The association of basal FSH with cancellation rate was significant with a predictive value of 79% and was independent of and stronger than the effects of age and inhibin B (P < 0.05). Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate. Menstrual irregularities. The clinical community generally accepts that hormonal therapy is highly successful at treating DUB. A 2004 study by Hurskainen et al. (30) followed more than 200 women with DUB who were treated with a triphasic preparation of norgestimate and ethinyl E2. More than 80% were documented to have improvement in bleeding, and this was significantly increased over the placebo group. The authors concluded that the triphasic combination of norgestimate and ethinyl E2 is an effective treatment for metrorrhagic, menometrorrhagic, oligomenorrhoeic, and polymenorrheic dysfunctional uterine bleeding. General reproductive function. Linglart et al. (31) looked at the use of recombinant growth hormone on 64 young girls with Turner syndrome. 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. In 2012, Lee et al. (32) studied 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% E2 suppression. The authors concluded that treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis.

The cost of an FSH 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. By contrast, an AMH test costs around US$ 100 in the USA, US$ 17–28 in India, US$ 64 in Australia and US$ 80.50 in Uganda. It is several times more expensive to predict IVF success through ultrasound determination of follicle number and size. An FSH measurement that prompts patients to abandon a cycle of assisted reproductive technology could result in significant savings (thousands of dollars in the USA). It is also relatively inexpensive to determine whether anovulation has occurred using an FSH measurement, particularly in cases of amenorrhoea. Given the significant syndromes and health issues that are associated with anovulation, such as disorders of sexual development or PCOS, there should be no question that confirming anovulation and reducing its morbidity would be cost-effective. Identifying anovulatory women also allows preventive 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 at €37 billion every year in the European Union, and US$ 19 billion 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.

FSH measurement plays a significant role in the diagnosis and management of 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 FSH as an infertility diagnostic test can be appreciated. FSH levels are also used to identify DSDs attributable to hypogonadism, and identifying these disorders is essential to prevent further illness and death. 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. Measurement of FSH levels should be accessible to most global populations. Its use will reduce inequalities, provided that health care systems are both equipped and prepared to follow through and make available the treatments that are indicated by the results.