Secondary Hypogonadism - Data On The Causes? Prevalence of Pituitary Lesions?

[bennettjc]

I often find myself giving advise to guys who are started on TRT who have not had any sort of thoughtful evaluation of the etiology of their hypogonadism.

The question comes up of whether or not to recommend an MRI of the pituitary. As someone whose hypogonadism may be due to a pituitary lesion I do wonder if there is any sort of breakdown, with %s, of the causes of secondary hypogonadism or hypogonadism in general? I've searched and have had no luck. Many review articles have lists but no numbers. Presumably the lists start off with the most common causes but that is by no means clear.

 

[madman]

I often find myself giving advise to guys who are started on TRT who have not had any sort of thoughtful evaluation of the etiology of their hypogonadism.

The question comes up of whether or not to recommend an MRI of the pituitary. As someone whose hypogonadism may be due to a pituitary lesion I do wonder if there is any sort of breakdown, with %s, of the causes of secondary hypogonadism or hypogonadism in general? I've searched and have had no luck. Many review articles have lists but no numbers. Presumably the lists start off with the most common causes but that is by no means clear.

Adult-Onset Hypogonadism (2016)

The Sexual Medicine Society of North America defines adult-onset hypogonadism (AOH) as a clinical and a biochemical syndrome characterized by a deficiency of testosterone (T) with symptoms and signs that can be caused by testicular and/or hypothalamic-pituitary (HP) dysfunction; AOH is therefore clinically distinct from classical primary and secondary hypogonadism. This syndrome is characterized by T deficiency and the failure to mount an adequate compensatory pituitary response to low T levels; gonadotropin levels are low or in the normal range.

Hypogonadism is classically defined as primary or secondary. Primary hypogonadism (hypergonadotrophic hypogonadism) is the result of testicular failure to produce adequate levels of T, and is identified by low T and elevated gonadotropin levels (luteinizing hormone [LH]; follicle-stimulating hormone [FSH]). Secondary hypogonadism (hypogonadotrophic hypogonadism) is the result of gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency (eg, pituitary or hypothalamic failure), which may be congenital or may arise from various pathological processes including HP injury from tumors, trauma, or radiation.




Pathophysiology

The classical framework for the diagnosis of hypogonadism uses the anatomic approach that is shared with other endocrine disorders. Primary testicular disorders impair both Leydig and seminiferous tubule function, resulting in reduced T synthesis and hypospermatogenesis. The etiologies include XXY karyotype (Klinefelter syndrome), toxicities (chemotherapy-induced), infectious destruction (mumps orchitis), or radiation-induced damage. The hormonal pattern is a low serum T level with elevated serum gonadotropin levels. Secondary hypogonadism also called centrally mediated hypogonadism, is classically due to destruction or infiltration of the pituitary gland, resulting in reduced gonadotropin synthesis and low circulating T level. Etiologies include pituitary tumors (secretory or nonsecretory), granulomatous invasion, or infectious complications. Some patients have congenital or acquired disorders resulting in LHRH (gonadotropin-releasing hormone [GnRH]) deficiency.

Many chronic illnesses are associated with low T levels but do not fit into the 2 classical endocrine situations described above. These syndromes, with clinical symptoms of hypogonadism, are acquired in adulthood and often exhibit functional hyposecretion at the level of both pituitary and testis.




Prevalence of AOH

One of the challenges of diagnosing and treating AOH is that its true prevalence is unclear. Epidemiological studies vary in how androgen deficiency (AD) was defined and in whether signs and symptoms were considered. In addition, even when men are categorized as having primary vs secondary hypogonadism, the designation of secondary hypogonadism does not establish the extent to which the low T level is truly the consequence of inadequate gonadotropins - some of these men may well have a primary testicular failure component. The breakdown of the primary vs secondary distinction highlights the need for a more accurate definition of these patients (eg, AOH). These studies provide useful information, however, given that AOH is conceptualized as a subgroup of men with signs and symptoms who have an inadequate pituitary response to low T levels.

In the EMAS, the prevalence of hypogonadism was 13.8%; of these men, 85.5% were classified as having secondary hypogonadism.4 The prevalence of hypogonadism in a group of 990 men seeking care for sexual dysfunction was 36% (359); of these men, 83.8% (301 out of 359) had secondary hypogonadism.5 Similarly, 87.1% (727/835) of men with hypogonadism were classified as having secondary hypogonadism by Maseroli et al6 when reporting on a large series of patients presenting at an emergency department clinic (n¼3847). Another report on an overlapping cohort from the same clinic noted that approximately 87.5% (724/827) of men with hypogonadism had secondary hypogonadism.7

Importantly, among men with secondary hypogonadism, only 11% had a specific medical condition (eg, genetics, surgery, radiotherapy, and trauma) that could account for the hypogonadism; the etiology in the remaining 89% was unknown8 (see Figure 2). The term AOH could be applied to the overwhelming majority of these men, many of whom also had concomitant metabolic disease (ie, obesity, type 2 diabetes [DM2], or metabolic syndrome [MetS]; see Figure 3). It is noteworthy that Camacho et al9 reported that weight gain and obesity are significantly associated with low total T and low free T levels.

When symptoms are part of the hypogonadism definition, the prevalence is lower. The Boston Area Community Health (BACH) Survey assessed symptomatic AD in a population of 1475 randomly selected men aged 30 to 79 years.10 Approximately 5.6% of men met the criteria for symptomatic AD, which was defined as low total or free T levels in addition to having low libido, erectile dysfunction, osteoporosis or fracture, or having 2 or more of the following symptoms: sleep disturbance, depressed mood, lethargy, or diminished physical performance. In the EMAS, 2.1% of men had symptomatic late-onset hypogonadism (LOH), defined as low total and free T levels with at least 3 sexual symptoms.11

EVALUATION AND MANAGEMENT OF TESTOSTERONE DEFICIENCY: AUA GUIDELINE (2018)

Pituitary Disorders.

Pituitary dysfunction may be a significant cause of testosterone deficiency. The pituitary gland sits in the sella turcica below the cerebrum and plays a critical role in testosterone physiology by producing luteinizing hormone (LH), which targets the Leydig cells in the testes stimulating them to produce testosterone. Serum testosterone and the downstream hormone E2 are involved in the feedback mechanism to the hypothalamus and pituitary to suppress LH production. In homeostasis, LH levels are typically low. With worsening Leydig cell function, there is a reduction in the feedback mechanism resulting in elevation of LH levels (hypergonadotropic hypogonadism). In conditions where LH is not produced in normal amounts (hypogonadotropic hypogonadism), testosterone deficiency may also result. The most common clinical causes of pituitary-associated hypogonadotropic hypogonadism include prolactinoma, pituitary radiation, pituitary removal, hemochromatosis/iron overload, and certain para sellar processes. Functioning prolactinomas result in hyperprolactinemia, suppressing LH production and leading to low testosterone levels. The contemporary management of functioning prolactin-secreting tumors is the use of medications, such as bromocriptine and cabergoline. Large pituitary tumors, functioning or nonfunctioning, may require surgical extirpation because of the mass effect. Radiation to the brain that exposes the pituitary gland can also result in pituitary dysfunction and low testosterone. The hypothalamic-pituitary unit is highly radiosensitive. Thus, pituitary dysfunction can develop after radiation therapy for sellar, parasellar, and extrasellar neoplasms (e.g., craniopharyngiomas, meningiomas, germinomas, chordomas, hemangiopericytomas, pituicytomas, gliomas), head and neck tumors, and following total body irradiation for systemic malignancies. Depending upon the radiation dose, delivery modality, and underlying tumor type, LH deficiency rates in patients whose pituitary gland has been exposed to radiation is 10-96%.160




Adjunctive Testing

6. In patients with low testosterone, clinicians should measure serum luteinizing hormone levels. (Strong Recommendation; Evidence Level: Grade A)

LH, which is routinely measured by immunoassay, may help to establish the etiology of testosterone deficiency and can be an important factor in determining if adjunctive tests should be ordered (Appendix C). A low or low/normal LH level points to a secondary (central) hypothalamic-pituitary defect, (hypogonadotropic hypogonadism), while an elevated LH level indicates a primary testicular defect (hypergonadotropic hypogonadism).168

*In men with hypogonadotropic hypogonadism, the yield from adjunctive tests (e.g., prolactin measurement, pituitary imaging, iron studies) is increased. However, the literature at this time fails to define the LH level below which such adjunctive testing is warranted.

*Hypogonadotropic hypogonadism can result from a number of conditions, including congenital abnormalities (e.g. Kallman syndrome), as well as pituitary or suprasellar tumors, pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis), medications (i.e. chronic narcotic exposure), hyperprolactinemia, prior head trauma, pituitary apoplexy, and severe chronic illness. In the event that a patient may have hypogonadotropic hypogonadism, adjunctive tests should be ordered.

Hypergonadotropic hypogonadism, which is not a contraindication to begin testosterone therapy, can result from a number of conditions, including congenital abnormalities (KS being the most common), iatrogenic causes (e.g., bilateral orchiectomy, testicular radiation, chemotherapy), testicular trauma, infection, or autoimmune damage. In some cases, the etiology is obvious (e.g. iatrogenic causes), in others, a karyotype may be warranted to establish a diagnosis of KS (47, XXY).169 In other cases, it may not be possible to establish a definitive etiology

Testosterone deficient patients with low or low/normal LH levels can be considered candidates for SERM use as a treatment for testosterone deficiency, particularly those wishing to preserve their fertility.170 However, an LH level below which SERM response is optimized is not firmly established.




7. Serum prolactin levels should be measured in patients with low testosterone levels combined with low or low/normal luteinizing hormone levels. (Strong Recommendation; Evidence Level: Grade A)

In patients who have low total testosterone and low or low/normal LH levels (hypogonadotropic hypogonadism), serum prolactin should be measured to screen for hyperprolactinemia (Appendix C).168, 169 If a patient has elevated prolactin levels, prolactin measurement should be repeated to ensure that the initial elevation was not spurious. Men with total testosterone levels of <150 ng/dL in combination with a low or low/normal LH should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified.171




8. Patients with persistently high prolactin levels of unknown etiology should undergo evaluation for endocrine disorders. (Strong Recommendation; Evidence Level: Grade A)

Hyperprolactinemia is an uncommon condition172, 173 but it is a well-established cause of secondary (central) testosterone deficiency and can lead to infertility, decreased libido, sexual dysfunction, and gynecomastia. Medications, most commonly dopamine antagonists (but also anti-psychotics, anti-emetics, proton pump inhibitors, calcium channel blockers, opiates, and selective serotonin reuptake inhibitors) may cause hyperprolactinemia.173 Chronic medical conditions, such as hypothyroidism, renal failure, and cirrhosis are associated with hyperprolactinemia as well.174

Persistently elevated prolactin levels can indicate the presence of pituitary tumors such as prolactinomas,175 the most common functioning pituitary tumor. Current literature fails to support any specific level of prolactin elevation that is predictive of prolactinomas, however, any persistent elevation in prolactin level may be associated. While prolactin levels generally parallel tumor size, most are typically associated with prolactin levels above 250 mg/L,175 although levels can exceed 1,000 mg/L.176 Milder elevations in prolactin can be seen with prolactinomas as well as with other pituitary or parasellar tumors or infiltrative processes.176, 177

Patients should be referred to an endocrinologist for further evaluation if the etiology for hyperprolactinemia cannot be established. An evaluation for prolactinoma in such patients is imperative because these benign tumors can be effectively managed using medications, such as bromocriptine or cabergoline. Furthermore, the identification of other pituitary tumors or processes may have important clinical implications for the patient beyond testosterone deficiency.178




Test
Pituitary MRI

Indication
Men with sustained elevated prolactin levels, very low total testosterone levels (<150 ng/dL), and unexplained failure to produce LH/FSH warrant a pituitary MRI to identify sellar (pituitary adenoma, prolactinoma, infiltrative diseases of the pituitary) or parasellar processes.

Clinician Response
The clinician may decide to refer such patients to an endocrinologist prior to ordering an MRI or may order the MRI first and refer only for abnormalities.

For clinicians experienced in managing prolactinomas, bromocriptine or cabergoline may be prescribed without endocrinology input.

 

[bennettjc]

Thank you!

As you are the responder...I suspect that what I am looking for simply doesn't exist.

But, to extract, in one study about 85% of hypogonadism is secondary. And in secondary hypogonadism in only about 10% could a specific etiology be identified.

As far as the treatment guidelines go, I've always had mixed feelings about these. They have good points and bad points. All that I conclude for sure is that they are rarely followed, for better or worse.

Some responses to the guidelines:
-I do like that they mention only LH as being helpful to follow-up low testosterone levels. FSH is always said in the same breath, including by me. I'm going to stop.

-It is impractical, though, to wait for the LH result to come back before ordering (or not) the Prolactin level.

-Glad to see that they recommend the MRI no matter the prolactin level. But I think their 150ng/dl Total Testosterone cutoff is unhelpful given how much testosterone fluctuates.

 

[Cataceous]

Purely my own impression: I suspect that a majority of idiopathic secondary hypogonadism has hypothalamic origins. There is greater complexity there, and thus more chance for something to go wrong. For example, you've got kisspeptin, neurokinin B and dynorphin all playing a role in GnRH regulation. At the pituitary it seems to be a more straightforward process of GnRH driving LH production, modulated by estradiol.

You can differentiate by performing a GnRH stimulation test, but nobody bothers because at present it doesn't change the treatment.