Sex hormones and SHBG in blood

SHBG binds testosterone and thereby determines how large the free fraction is. The binding is saturable, which makes the relationship between total and free testosterone non-linear: the lower the SHBG, the larger the part of the total that is left free. A drop in SHBG therefore raises free testosterone more than you would expect on the basis of the total.

What lowers SHBG

• Insulin resistance and a high insulin, and with that overweight and a lot of visceral fat
• Androgens, and most strongly the orally active, alkylated variants
• Growth hormone and a high IGF-1
• Glucocorticoids
• A slow thyroid
• Protein loss, as in nephrotic syndrome

What raises SHBG

• Estrogen, naturally or from outside
• Thyroid hormone: with hyperthyroidism SHBG clearly rises
• Liver disease, particularly cirrhosis
• Energy deficit, underweight and prolonged hard dieting
• Aging
• Some medicines, including antiepileptics

That also makes SHBG an indirect metabolic marker. An SHBG at the bottom of or below the range in someone using nothing is a reason to look at fasting glucose, HbA1c and the lipids. See the chapter on hormones and cardiovascular risk.

Calculated or directly measured

There are three ways a free testosterone ends up on a report.

• Calculated, usually with the Vermeulen formula, from total testosterone, SHBG and albumin. Cheap, reproducible and good enough for practice. If albumin is missing, the laboratory fills in an assumption, which introduces an error with an abnormal albumin.
• Equilibrium dialysis, preferably with mass spectrometry. This is the reference method, but costly and not available everywhere.
• Direct analog immunoassay. This is advised against in guidelines, precisely because it goes wrong with an abnormal SHBG, exactly where you need it.

Practically: if there is a free testosterone on the report without SHBG alongside it, assume you cannot check the value. If SHBG is there, you recalculate the free fraction yourself by dividing free testosterone in nmol/l by total testosterone. High in the reference that should come out at roughly 2 percent.

With sex hormones the conditions of the draw can make the difference between normal and abnormal. The rules are simple and not negotiable once you want to be able to compare measurements.

• In the morning, preferably between 7 and 10. Testosterone has a daily rhythm with a peak in the early morning and a trough in the afternoon. In young men that difference is largest; an afternoon measurement can make a healthy man come out unjustly low.
• Fasted. A meal, and certainly a carbohydrate load, lowers total testosterone measurably within an hour. Drawing fasted takes that noise out and delivers glucose, insulin and lipids immediately usable.
• Not right after hard training. Strength training gives an acute rise through hemoconcentration and a response of the axis, and in the days after it actually a dip. Keep 24 to 48 hours of rest before the draw, and at every subsequent measurement the same gap since the last training.
• Not during illness or shortly after. An infection, fever or a period of poor sleep suppresses the axis. Postpone the measurement to at least two weeks after recovery.
• Well hydrated and without alcohol the evening before. Dehydration raises all protein-bound values, including hematocrit.
• Stop biotin. High doses of biotin, including from hair and nail supplements, disturb many immunoassays and can make hormone values falsely high or falsely low. Follow the laboratory's instruction, in practice stopping 48 to 72 hours beforehand.
• Sit quietly before the draw, certainly if prolactin is on the request. Needle anxiety, rushing and a hurried journey to the lab raise prolactin. Twenty to thirty minutes of sitting before the draw is enough.
• With injections always at the same point in the interval. Where in the dosing interval you draw determines the result entirely. The usable agreement is just before the next dose, and recording that moment alongside the result.

Beyond that, what the chapter on interpretation and reference values says applies: the same laboratory, the same assay method and the same time, otherwise you compare two things that are not comparable. An abnormal testosterone is moreover never concluded on a single measurement; a second measurement on another morning is the standard.

In men practically all estradiol comes from aromatization of testosterone, especially in fat tissue. So it is not a female hormone that is there by accident, but a necessary metabolite. Estradiol contributes to bone density, libido and erectile function, fat distribution, joint comfort, mood and the lipid profile. See level 4 for the mechanism.

The often-heard idea that lower is always better is therefore wrong. Too low an estradiol gives just as many complaints as too high an estradiol, and partly the same ones. Too high gives fluid retention, a bloated feeling, mood swings and sensitive breast tissue. Too low gives dry and painful joints, loss of libido, erectile problems, listlessness, a less favorable HDL and in time bone loss. If the value is knocked down with an aromatase inhibitor, you see those complaints appear within weeks.

Two things to watch when reading an estradiol value:

• The assay method. The common immunoassay is designed for the much higher concentrations in women and is imprecise in men, with cross-reactivity that can inflate the result. A sensitive assay or mass spectrometry is more reliable. With an unexpected result, ask which assay was used.
• The ratio to testosterone. Estradiol moves along with the testosterone it arises from. A high estradiol with a high testosterone is expected physiology. What you have to look at separately is an estradiol moving the opposite way from the testosterone.

As a coach you do not steer on an estradiol number. You lay the value alongside the complaints and the course, and you refer to the physician as soon as treatment comes into view.

LH and FSH tell you whether the body's own drive is still running. LH drives testosterone production in the testis, FSH the sperm production. The combination with testosterone reads as follows:

• Low testosterone with a low or inappropriately normal LH and FSH: the drive itself is faltering, or there is a source from outside.
• Low testosterone with a raised LH and FSH: the testis no longer responds and the axis is trying harder.
• High testosterone with a suppressed LH and FSH: the testosterone comes from outside. At supraphysiological values LH and FSH are practically always immeasurably low.

A high testosterone with a normal LH is internally contradictory and a reason to doubt the draw or the assay. After stopping a source from outside LH comes back earlier than total testosterone, and full recovery takes months, not weeks.

Prolactin is often requested and almost as often read wrongly. A slightly raised value is rarely a tumor. The most important causes, in order of likelihood:

• Measurement stress. The venipuncture itself, rushing or needle anxiety raises prolactin. This is the most common explanation for a slightly raised result.
• Recent waking, sleep shortage, sexual activity and nipple stimulation in the hours before the draw.
• Macroprolactin. Prolactin bound to an antibody forms a large complex that is not biologically active, but does count in the assay. This is an artifact, not a disorder. The laboratory can rule it out with a PEG precipitation, but you have to ask for that separately.
• A slow thyroid. With hypothyroidism prolactin rises along. So always look at TSH and free T4 on the same report.
• Medication, including antipsychotics, some antidepressants, gastric drugs such as metoclopramide and domperidone, and some blood pressure lowering drugs.
• Substances with a progestogenic action, including the 19-nortestosterone derivatives.
• A prolactinoma. This belongs on the list, but sits at the bottom because with a slight rise it is rarely the explanation. With a considerably raised value, or with headache and loss of visual field, the client goes to the physician immediately.

The practical rule: you repeat a slightly raised prolactin under correct conditions before you form an opinion about it.