Symptoms to Diagnosis

An obese 48-year-old man with progressive fatigue and decreased libido

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His physician orders testing of serum LH and FSH, yielding the following values:

  • LH 1.6 mIU/mL (reference range 1.8–12)
  • FSH 1.9 mIU/mL (reference range 1.5–12.5).

The diagnosis of central hypogonadism is established.

3. Which investigation is the least appropriate in the further evaluation of this patient?

  • Table 4. Causes of central hypogonadism
    Serum free thyroxine (T4) and morning cortisol measurement
  • Serum prolactin measurement
  • Serum ferritin measurement
  • Pituitary magnetic resonance imaging (MRI)
  • Chromosomal karyotyping

The diagnosis of central hypogonadism warrants evaluation for possible causes. These are summarized in Table 4.

Serum free thyroxine and morning cortisol

Since this patient’s LH and FSH values are abnormal, it is important to evaluate the status of other anterior pituitary hormones. In patients with pituitary abnormalities, serum free T4 is a more reliable test for assessing thyroid function than thyroid-stimulating hormone (TSH), because of loss of the negative feedback of thyroid hormones on the diseased pituitary. In contrast, serum TSH is considered the best single thyroid test to assess primary thyroid dysfunction.

Other measurements include prolactin and morning cortisol (reflecting adrenocorticotropic hormone status).

Prolactin measurement

Prolactin measurement is important to evaluate for hyperprolactinemia, as this will lead to hypogonadism by inhibition of GnRH secretion.25 Different pathologic, pharmacologic, and physiologic conditions can result in hyperprolactinemia, including prolactinomas, other pituitary and hypothalamic lesions, primary hypothyroidism, and medications such as antipsychotics.25 Dopamine agonists are the mainstay treatment for hyperprolactinemia.

Ferritin measurement

Ferritin measurement is indicated to diagnose iron overload conditions such as hemochromatosis, which can result in primary hypogonadism via testicular damage or in secondary hypogonadism via pituitary damage.26

Pituitary MRI with contrast

Pituitary MRI with contrast is used to diagnose structural lesions of the pituitary or hypothalamus. This diagnostic modality is indicated for patients with pituitary dysfunction, including central hypogonadism, manifestations of a mass effect (headache, visual field defects), persistent hyperprolactinemia, and panhypopituitarism, among others. To improve the diagnostic yield of pituitary MRI, the Endocrine Society guidelines recommend it for men with serum total testosterone levels below 150 ng/dL.5 However, some clinicians have a lower threshold for ordering pituitary MRI for patients with central hypogonadism. Physician judgment and expertise should be exercised and the decision made on an individual basis.

Chromosomal karyotyping

Chromosomal karyotyping is not indicated in our patient. It is reserved for those with primary hypogonadism to diagnose Klinefelter syndrome, which has a karyotype of 47,XXY.


Our patient’s prolactin, free T4, morning cortisol, and ferritin levels are measured, yielding normal values. No abnormalities are seen on pituitary MRI. A clinical reevaluation is conducted, revealing no history of head trauma or head and neck radiation. The lack of an obvious cause in our patient’s clinical presentation and workup, together with his obesity (BMI 32.8 kg/m2) supports the diagnosis of obesity as the cause of his hypogonadism.

Obesity can be a cause of secondary hypogonadism, which has led to the term “MOSH” (male obesity-associated secondary hypogonadism) syndrome. In fact, a cross-sectional study has demonstrated that 40% of nondiabetic obese (BMI ≥ 30 kg/m2) men over age 45 have low serum free testosterone levels, compared with 26% for lean (BMI < 25 kg/m2) men.27 Moreover, obesity has been found to be a strong predictor of testosterone replacement therapy.28 Other studies have also found an inverse relationship between BMI and testosterone levels.29

Several mechanisms interact in the pathogenesis of MOSH syndrome. Adipose tissue possesses aromatase activity, which converts androgens into estrogens.30 Peripheral estrogen production can in turn exert feedback inhibition on pituitary gonadotropin secretion.31 In obese men, increased adipose tissue leads to increased aromatase activity and more estrogen, so more feedback inhibition on the pituitary and subsequently secondary hypogonadism. 

Leptin, a hormone produced by adipocytes, is also increased in obesity, and was found to be inversely correlated with serum testosterone.32 Studies have demonstrated that leptin has an inhibitory effect on the enzymatic pathway that synthesizes testosterone in Leydig cells.33

Proinflammatory cytokines have also been implicated, as central obesity is associated with an increase in these cytokines, which in turn act negatively on the hypothalamus and impair GnRH release leading to lower testosterone.34,35

Treating obesity-related hypogonadism

In a pilot study,36 lifestyle attempts to reduce obesity were shown to improve hormonal levels. Bariatric surgery has also been demonstrated to be successful.37

Clomiphene citrate, a selective estrogen receptor modulator, increases endogenous testosterone secretion by inhibiting the negative feedback of estrogen on the hypothalamus and pituitary and thus increasing LH and FSH. It also preserves endogenous testosterone production, since it does not suppress the hypothalamic-pituitary-testicular axis.38 This made clomiphene citrate a potential treatment for men with central hypogonadism including those with MOSH.39

Nevertheless, there are no randomized trials to prove its safety and efficacy in the management of central hypogonadism.5 Regarding its use in men wishing to preserve fertility, most studies did not show improvement. However, a meta-analysis demonstrated statistically significant increased pregnancy rates in partners of men with idiopathic infertility if the men used 50 mg of clomiphene citrate daily.40

Testosterone deficiency can be a marker of metabolic syndrome, which needs to be managed more urgently than hypogonadism. A cross-sectional study found not only an association between metabolic syndrome and low serum testosterone, but also with each individual component of metabolic syndrome on its own, all of which need to be addressed.10

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