Boys and girls may equally have multiple pituitary hormone deficiencies across all levels of peak growth hormone values, according to a study recently published in Clinical Endocrinology.
The paper, by Rohan K. Henry, MD, MS, et al., outlines reported biases which have long been published regarding the male predominance in patients referred to pediatric endocrinology clinics, those who undergo growth hormone provocation testing and ultimately those who are diagnosed with growth hormone deficiency (GHD).
Henry, an attending physician in the Section of Endocrinology at the Nationwide Children’s Hospital, in Columbus, Ohio, and associate professor at the Ohio State University College of Medicine, says that he has been in clinical practice for more than a decade and he has noticed that patients referred to their clinics are predominantly male. He says the literature is also replete with publications that attest to the predominantly male distribution of patients receiving growth hormone supplementation for indications of growth hormone deficiency and non- growth hormone deficient states.
“Though some of these articles tackle the origins of the male sex predominance of patients referred to endocrine clinics, those who undergo growth hormone provocative testing (which is often performed to confirm the clinical diagnosis of GHD) and those who are ultimately diagnosed with GHD, there has been a gap in the literature as the authors of the currently published papers have not attempted to try to minimize the biases so that a more realistic sex distribution regarding GHD can be obtained,” Henry says.
Henry goes on to say that unlike some conditions that do have a biological basis for male/female predilection, such as the female predominance of auto-immune disease, it seems biologically implausible that those impacted by GHD should be primarily male. “As such, we sought to look at the diagnosis of GHD under different frameworks, which, though used in clinical practice, namely the peak growth hormone level obtained during provocative testing which is sometimes used to indicate GHD severity that could be deemed as an arbitrary designation,” he says. “Whereas the others, such as the presence of multiple hormonal deficiencies and abnormalities on pituitary gland magnetic resonance imaging, could indicate an organic etiology as the basis for GHD.”
Henry tells Endocrine News that there are three main biases that impact the sex distribution of patients attending the endocrinology clinic for growth evaluation: selection bias, in which parents are more concerned with the height of boys more so than girls; referral bias, as more male children are referred for growth concerns; and provider bias, where there’s a predominantly male referral pattern and it has been shown that more diagnostic tests are performed in evaluating boys as compared to girls for short stature. “It has also been shown that more boys than girls receive provocative tests for GHD,” he says. “While these biases cannot be prevented, to obtain the true sex distribution of GHD, they need to be minimized from a methodological standpoint in any study which attempts to address the gap in the literature regarding the true sex distribution of GHD.”
For this study, the researchers use three different frameworks, two of which were designed to minimize the male sex bias. These frameworks involve an examination of cases of GHD based on 1) peak growth hormone values, 2) the presence of isolated GHD vs multiple pituitary hormone deficiencies and 3) the presence of anatomical abnormalities of the pituitary gland on magnetic resonance imaging. “It is noteworthy that when the sex distribution in pediatric GHD cases was examined using frameworks 2 and 3, the historically reported male sex distribution was not present,” Henry says.
A retrospective chart review was conducted that looked as to whether there were sex differences in those referred to the endocrinology clinics, those who underwent growth hormone provocation testing and ultimately those who were diagnosed with GHD. In all these instances, there was a male predominance (p < 0.001). It also looked as to whether there are sex differences based on GHD severity using peak growth hormone values as a surrogate.
The results showed that there was a difference in peak GH values used as a surrogate for GHD severity and sex, and there was no difference in the frequency of GHD between the sexes when GHD existed within the setting of multiple pituitary hormone deficiencies. Similarly, there was no difference in the frequency of GHD between the sexes when abnormalities existed in pituitary magnetic resonance imaging. “So with using the latter 2 frameworks, there is minimization of the biases which results from framework 1 in which GHD is idiopathic,” Henry says.
One of the implications of these findings is that girls who are diagnosed with GHD may present later for care; fewer girls will be diagnosed with GHD compared to boys. “This could mean that treatment may be delayed which could be detrimental especially those who need to be replaced with growth hormone in addition to other hormonal supplementation,” Henry says. “Moreover, it has been shown previously that girls, especially underrepresented girls, may be diagnosed later with conditions which are associated with the etiology of short stature.”
“Despite the well-known male predominance in pediatric endocrinology clinic referrals for short stature, those who undergo provocation testing for GHD, and those ultimately diagnosed with GHD, there is unlikely to be a true sex difference in patients diagnosed with more permanent or organic causes of GHD, such as those with multiple pituitary hormonal deficiencies and also with abnormalities pituitary magnetic resonance imaging,” Henry continues. “In addition, the male predominance in GHD may reflect an over diagnosis of idiopathic GHD in boys and this may exist due to current limitations in accuracy surrounding the diagnosis coupled with the biases which result in more males accessing medical care for short stature evaluations.”
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