Secondary Hypogonadism, Stress, and the HPA Axis: What the Evidence Shows

What does the HPA axis do to GnRH, LH and FSH?

The hypothalamic-pituitary-adrenal axis is the body's stress circuit: the hypothalamus releases corticotropin-releasing hormone (CRH), the pituitary releases adrenocorticotropic hormone (ACTH), and the adrenal cortex releases cortisol.

A 2010 review of glucocorticoids and fertility describes action at three levels: the hypothalamus, where glucocorticoids decrease the synthesis and release of GnRH; the pituitary, where they inhibit the synthesis and release of LH and FSH; and the gonad itself, where they can modulate steroidogenesis directly [1]. The testosterone labels describe the lab split that separates the two types: primary hypogonadism usually shows low testosterone with LH and FSH above the normal range, while hypogonadotropic hypogonadism shows low testosterone with LH and FSH in the normal or low range [3].

What the human evidence shows

The clearest study identified here is not a study of psychological stress. It followed 21 cadets through two separate 5-day military endurance courses with physical activity around the clock, a daily energy expenditure of about 40,000 kilojoules against an intake of about 2,000 kilojoules, and 1 to 3 hours of sleep across the five days [2]. Testosterone, free testosterone, DHEA, 17-alpha-hydroxyprogesterone and androstenedione fell by 60 to 80 percent. Cortisol, aldosterone, progesterone and DHEAS rose, and LH, FSH and ACTH fell to about 50 to 80 percent of precourse levels [2]. Falling testosterone alongside falling rather than rising gonadotropins is in the direction of the hypogonadotropic pattern described on the labels [3]. The authors concluded that both adrenal and testicular androgens decrease during prolonged physical strain combined with energy and sleep deficiency [2].

How is secondary hypogonadism diagnosed?

Diagnosis is based on symptoms and signs plus consistently low fasting morning testosterone confirmed by repeat testing; LH and FSH help identify the cause [4][5]. The Endocrine Society guideline recommends a fasting morning total testosterone on an accurate and reliable assay as the initial test, confirmed by repeating it; if total testosterone is near the lower limit of normal, or a condition alters sex hormone-binding globulin, free testosterone by equilibrium dialysis or an accurate formula is used [4]. The AUA guideline uses a total testosterone below 300 ng/dL as a reasonable cutoff and requires two early-morning measurements on separate occasions [5]. For context, in healthy non-obese men aged 19 to 39 the harmonized 2.5th percentile is 264 ng/dL and the median is 531 ng/dL [8].

Once deficiency is confirmed, the Endocrine Society calls for further testing to find the cause, including LH and FSH to separate primary from secondary hypogonadism [4]. The secondary causes the labels name are gonadotropin or LHRH deficiency and pituitary or hypothalamic injury from tumors, trauma or radiation [3]. The Endocrine Society guideline does not recommend screening the general population [4].

What treatments are approved?

FDA-approved testosterone products are for men who lack testosterone or have low testosterone together with an associated medical condition, such as testicular failure or a hypothalamus or pituitary problem; FDA states that none is approved for men with low testosterone who lack such a condition [6]. Hypogonadotropic hypogonadism is a labeled indication for testosterone [3][9].

The trade-off that matters most on this page is fertility. Exogenous testosterone suppresses spermatogenesis, and the Endocrine Society recommends against starting testosterone in men who are planning fertility in the near term [4].

For men who want to preserve fertility, the approaches described are hCG and selective estrogen receptor modulators. Human chorionic gonadotropin is FDA-approved for selected cases of hypogonadotropic hypogonadism (hypogonadism secondary to a pituitary deficiency) in males [7]. A 2013 review of treatment in men of reproductive age describes hCG or selective estrogen receptor modulators as the approaches that protect the testis, and notes that off-label clomiphene citrate is effective for maintaining testosterone long term [10].

Clomiphene is approved only for ovulatory dysfunction in women, so its use in men is off-label [11]. A study of 46 men treated with clomiphene for more than a year reported mean testosterone rising from 228 ng/dL at baseline to 612 ng/dL at 1 year, 562 ng/dL at 2 years and 582 ng/dL at 3 years [12]. Enclomiphene is not an FDA-approved drug in any form [13]. Anastrozole is approved for breast cancer in postmenopausal women, not male hypogonadism [14], and the 2013 review does not recommend routine aromatase inhibitor use because long-term data are lacking [10].

Does anything else change testosterone?

A 2011 review of low testosterone in men with type 2 diabetes concluded that the key response is lifestyle measures such as weight loss and exercise, which, if successful, raise testosterone and provide other health benefits [15]. That evidence comes from men with type 2 diabetes and does not directly address low testosterone that follows prolonged physical strain and sleep loss.