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List of Acronyms/Abbreviations
BMD – Bone Mineral Density
BMI – Body Mass Index
CPP – Central Precocious Puberty
EBM- Evidence-Based Medicine
FSH – Follicle-Stimulating Hormone
GnRH – Gonadotropin-Releasing Hormone
GnRHa – Gonadotropin-Releasing Hormone Agonist
HPGa – the hypothalamic-pituituary-gonadal axis
LH – Luteinizing Hormone
PCOS – Polycystic Ovary Syndrome
UTD – UptoDate
List of Figures
Figure 1- Etiology and Mechanisms of Precocious Puberty………………………………………7
Central Precocious Puberty (CPP), also known as gonadotropin-dependent precocious puberty or true precocious puberty, is a condition defined by the presence of pubertal maturation 2 to 2.5 SD prior to population norms. CPP can also be defined as sexual maturation prior to age 8 in females and 9 in males. The causes of CPP can range from physiologic to pathologic. CPP is more prevalent in females. The gold standard for treatment of CPP is a gonadotropin-releasing hormone agonist (GnRHa). The issue with CPP is that it can have a long-standing risk of morbidity and death. Utilizing a GnRHa can have long term sequala as well, ranging from disturbances in long-term spatial memory, sexual function, Pseudotumor Cerebri development, phenotypic qualities and other pathologic effects. Follow up studies are required in order to validate the long-term sequela and ensure the accuracy of the sparse research.
Key Words: Central Precocious Puberty, gonadotropin-releasing hormone agonist, spatial memory, Pseudotumor Cerebri
Central Precocious Puberty (CPP) is the development of secondary sexual characteristics in boys prior to age nine and in girls prior to age eight. CPPs origin is thought to be the early development of the hypothalamic-pituituary-gonadal axis (HPGa). While the patients maturation happens in a sequential order and is gender appropriate, the onset of maturation is earlier. This early maturation causes accelerated linear growth, a disproportionate bone age and higher levels of follicle-stimulating hormone and luteinizing hormone. The gold standard treatment is a GnRHa, whose mechanism of action is to down regulate the pituitary gland and induce a hormonal prepubertal state. The utilization of a GnRHa can have both short-term and long-term sequela. While past research has shown that there are minimal long-term harmful effects, new research has emerged showing otherwise. The newest research indicates that utilizing a GnRHa has been linked to the etiology of Polycystic Ovary Syndrome (PCOS), spatial memory deficits and metabolic dysfunction. It is evident that more studies need to be done prior to proving these links.
Figure 1- Chart of the Etiology and Mechanisms of Precocious Puberty. Adapted from “Definition, Etiology, and Evaluation of Precocious Puberty-UptoDate.” Copyright by UptoDate.
The current climate of the medical field is that the side effects of GnRHa are reversible and there are no major long-term sequela. And while there are many studies which provide evidence towards this way of thinking, a growing body of studies have begun to show a potential for cognitive impact with utilization during the peripubertal period. A current thought process that will be addressed is the effect of GnRHa on spatial memory, sexual function, PCOS and final body composition. It is also evident that there is a lack of studies that have attempted to characterize the potential effects during the developmental period and that limited data has been obtained.
The main focus of this research is to determine whether the utilization of GnRHa, during the peripubertal period, will have long term seuquelae and whether the side effects will reverse upon discontinuation. Will sexual functioning be impacted? Will spatial memory deficits remain decades past discontinuation? Does treatment with a GnRHa increase the likelihood of one developing PCOS? Are GnRHa’s truly the gold standard for treating CPP? The questions specific to this research indicate an urgent need for further research on the long-term sequala of GnRHa’s.
Purpose of the Research
The purpose of this research is to explore the treatment of CPP and the residual effects of using a GnRHa. This meta-analysis will begin by discussing the pathophysiology of CPP and the mechanism of action of GnRHa’s. It will then dive into the short and long-term sequela of utilizing a GnRHa, while simultaneously proving that GnRHa’s are not as harmless as once theorized. In entirety, the purpose of this meta-analysis is to show that there are possible long-term risks associated with utilizing a GnRHa and further research needs to be conducted.
The bulk of this meta-analysis will come from a variety of literate resource databases, which whom Nova Southeastern University allowed access too. The major databases utilized were PubMed and UptoDate (UTD). I searched for keywords such as “CPP, GnRHa, GnRHa long-term sequela and treatment of CPP.” This research will utilize the most recent peer-review journals and articles, combined with evidence-based medicine (EBM).
GnRHa are the current gold standard treatment for CPP. Their mechanism of action is to provide negative feedback to the HPGa and create a prepubertal hormonal state. While many studies emphasize that GnRHa are harmless in the long term, a growing body of new research has proven that there are long-term consequences. The newest literature has shown a clear link between treatment with GnRHa, PCOS and long-term spatial memory deficits. While reviewing the current literature, I find that there is a definite gap in research that needs to be filled.
GnRH Agonists: The Gold Standard Treatment for CPP & The Long-Term Effects
Pathophysiology: Central Precocious Puberty
The main driving force behind CPP is the early maturation of the HPGa. While individuals with CPP will progress in a sequential pattern, their sexual characteristics will begin too early for their age. There is an early spike of luteinizing hormone and follicle-stimulating hormone, that will cause individuals to have advanced bone age and accelerated linear growth (Leger and Carel, 2017). CPP is idiopathic in 85% of the time in girls and 45% of the time in boys. A major pathologic cause of CPP is lesions of the central nervous system. This subset is more specifically known as neurogenic CPP. These CNS lesions range from hamartomas to astrocytomas. Other pathologic causes include exposure to irradiation, hydrocephalus, various cysts and inflammatory diseases.
Recent literature has pointed out a genetic correlation with CPP as well. The most prevalent mutation noted has been a gain-of-function mutation, specifically Kisspeptin 1 (K1SS1). It has been hypothesized that Kisspeptin 1 is integral in the initiation of the hormonal spike during the pubertal time window. Other notable mutations are two loss-of-function mutations, specifically makorin ring finger protein 3 (MKRN3) and Delta-like 1 homolog (DLK1).
A final hypothesis of the etiology of CPP that has been established, specifically is previous exposure to excess sex steroids. This is thought to be due to the priming effects steroids have on the hypothalamic drive (Definition, Etiology, and Evaluation of Precocious Puberty, 2018).
Mechanism of Action: GnRHa
The current gold standard, first line recommendation for CPP is a GnRHa. It is hypothesized that suppression of the pituitary gland is temporary and reversible. GnRHa initially stimulate the release of luteinizing hormone and follicle-stimulating hormone. However, overtime it ends up inhibiting the release of gonadotropin. In turn, this will decrease the linear growth velocity and thus increase the chances of the patient achieving standard adult height (Treatment of Precocious Puberty, 2018).
Short & Long-term Sequela:
Body Proportions & Composition:
There have been many studies done on utilizing GnRHa’s to help those with CPP achieve appropriate adult height. One study, which examined the impact GnRHa’s had on 50 young women with CPP, found that the mean full height of the women was around 160.6 cm or greater. They noted that this was far above the predicted height for these young women prior to treatment. All of these young women also achieved appropriate body proportions (Heger, Sabine, et al, 1999).
Another study that analyzed data on female patients with CPP, found that while it has been shown that treating patients with a GnRHa has the ability to ensure appropriate adult height, there was a pocket of control patient who reached their appropriate adult height as well. This study also showed that there is significant discrepancy in patient heights, making it hard to compare the results from those who are treated and those who are not treated. Thus, they concluded that it is hard to know how much of the increase in height is truly due to the GnRHa (Bereket, 2017).
The same study, discussed above, also examined bone mineral density (BMD) in these women. Neither osteoporosis or osteopenia were found to be short or long-term sequela. (Heger, Sabine, et al, 1999). Other studies have found that BMD tends to fluctuate throughout the treatment phase,. However, they ultimately found that there was no long-term decrease to bone mass s/p treatment (Kim, Eun Young, 2015).
A study performed on rats attempted to prove that a long-term treatment with a GnRHa induced apoptosis on various genes, with a special emphasis placed on the ovaries. When analyzing groups treated with GnRHa the researchers found that treatment drastically increased expression of cyt c gene and decreased expression of bcl 2 gene, both factors in the pathway of cellular apoptosis. It was also found that changes in gene expression promoted the formations of cysts on the rats ovaries. Thus, it has summated that GnRHa therapy can have lasting modulatory effects on apoptosis-related genes (“Long-Term Effects of GnRH Agonist, GnRH Antagonist, and Estrogen plus Progesterone Treatment on Apoptosis Related Genes in Rat Ovary,” 2009).
Long-term Spatial Memory:
A new growing body of studies show that GnRHa’s can have a lasting impact on spatial memory. A study done in rams examined giving them GnRHa’s during a “critical window,” defined as a time period when the hippocampus is more easily shaped. They found that if rams received treatment during this window, there would be a deficit in long-term spatial memory when compared with the control. They noted that the rams’ long-term spatial memory was 1.5-fold slower when compared with the controls at approximately 99 weeks s/p discontinuation (Bellingham, Evans, et al, 2017).
Obesity and Metabolic Syndrome:
There is conflicting evidence about the effect of treatment with a GnRHa on obesity. A study discussed earlier found that the effect of GnRHa on body mass index (BMI) has little to no effect. While the BMI only increased an average of 0.1% by the end of treatment in their patient population (Heger, Sabine, et al, 1999), other studies have shown that there was an increased in BMI from 0.93 to 1.2 and an increase in the frequency of obesity from 28% to 39% in their patients’ s/p treatment. Another study hypothesized that GnRHa decreased the incidence of obesity in their patient population. This confliction in the data shows that further research must be completed before any final decisions can be made (Kim, Eun Young, 2015).
Other studies on the matter of obesity have noted that the prevalence of obesity was already higher in those with CPP prior to treatment with a GnRHa (Yang et al, 2017). It was found that regardless of treatment, the BMI and obesity rates did not have a statistically significant change. Thus, the study concluded, that hormonal fluctuations that occur in CPP patients contribute more to the obesity rate than treatment with GnRHa’s (Palmert, Mark R., et al).
Another study found that while patients with CPP had a higher prevalence of obesity at the time of diagnosis, there was no change in BMI at the time treatment concluded. The study found that age of maturation, gender and duration of treatment also did not have an effect on BMI. The study also followed patients for 3 years following discontinuation. They concluded that BMI did not fluctuate s/p discontinuation of GnRHa. They actually found that patients with CPP, who did not receive treatment with GnRHa, maintained a higher BMI than those who received treatment (Guaraldi et al, 2016).
Polycystic Ovary Syndrome:
It has been proposed that treatment with a GnRHa in girls with CPP can increase the risk of developing Polycystic Ovary Syndrome (PCOS). The major theory behind this hypothesis is the over secretion of androgens and increased insulin resistance.
By comparing a treatment group with a control group, this study found that the incidence of PCOS was an average of 14.5% higher in those treated with GnRHa’s. It was noted that the treatment group had significantly higher levels of testosterone and dehydroepiandrosterone when compared to those that were not treated. The study was able to show that the prevalence of PCOS is approximately 4-12% in the general female population and 0-12% in those females’ s/p GnRHa discontinuation.
The study also looked at insulin sensitivity in those treated with GnRHa’s, finding that that it was decreased when compared to the control group. The study believes that GnRHa’s increase the levels of circulating androgens and decrease insulin sensitivity, which increases a patient’s risk for developing PCOS. Thus, it was summated that GnRHa therapy is an independent risk factor for developing PCOS (Chiavaroli, Valentina, et al, 2010).
Other studies have theorized that it is not the GnRHa that increases the incidence of PCOS, but the CPPs impact on the reproduction system. A working theory is that the hormonal spike seen in treatment with GnRHa’s and PCOS, has extremely similar mechanisms. It is even quite possible that CPP precedes PCOS due to the dysregulation of the endocrine system and HPGa. This study noted that 40% of those with CPP develop PCOS during the post-pubertal time period. However, the study still cited that the incidence of PCOS was higher in those treated with GnRHa’s when compared to the general population (Kim, Eun Young, 2015).
While rare, pseudotumor cerebri is a noted sequela of treatment with a GnRHa. One case study examined a 9-year-old girl whom suffered from CPP and was promptly treated. After the 4th injection, the girl developed pseudotumor Cerebri. The mechanism of action behind this is unknown. The current theory is that GnRHa’s causes a spike in serum androgens, which leads to an increase in venous pressure and decreases the drainage of cerebrospinal fluid. With treatment, this condition is completely reversible, and the patient should not suffer any long-term sequala (Gül, Ülkü, et al, 2016).
It has been hypothesized that continued treatment with a GnRHa will eventually inhibit the release of FSH and LH. One study done on boars found that continued treatment with a GnRHa will decrease the caliber of oocytes and inhibit the growth of follicles in females. In males, it was found to temporarily reduce fertility by reducing the production of sperm and inducing atrophy of the testes. All of the effects on sexual functioning were shown to be temporary and last no more than 6 months post discontinuation (Boehm, Kauffold, et al, 2010).
Another study was able to show that long-term treatment with a GnRHa can have a temporary effect on patient menstrual cycles, causing some to suffer from metrorrhagia. However, these effects were all temporary, ceased with discontinuation and patients were able to be treated with an oral contraceptive (Heger, Sabine, et al, 1999).
Implications for the PA Profession:
Through the process of researching this topic, I have noted that there are several findings that alter how PAs should approach patients with CPP. For instance, I noted that many studies indicated that patients with CPP often present with obesity and insulin resistance. The literature that many providers believe that by treating CPP with a GnRHa, the patients’ co-morbidities will also subside, however, no study has shown evidence to prove this though process. Thus, providers need to ensure that they do not just treat the patient for CPP, but the obesity and insulin resistance as well.
As stated above, new research has proposed that treatment with GnRHa can increase the incidence of PCOS in patients with CPP. While the link has not been definitely proven, providers need to be more alert of this possible long-term sequela. PCOS can have detrimental effects on patients’ health.
Strength of the Research:
Consistently throughout the literature, I have noted many notable strengths. A majority of the research discussed utilized large populations with both a cohort and a control group. The studies overall had generalizability. The studies also tended to follow the cohorts and controls for a long period of time, increasing the external and internal validity of the data and findings.
Weakness of the Research:
Throughout my research I noted many downfalls. The main weakness overall has been the lack of well-developed clinical trials. I also noted a lack of definitive evidence that showed a pathway link between GnRHa and the development of the harmful side effects, partially due to a lack of consistent data. A majority of the research performed was the first of its kind. Many studies that showed evidence of negative long-term sequala were the only ones to have either studied that topic or to have proven their hypothesis. And further, the studies were primarily performed on animals or utilized older patient data.
Recommendations for Future Research:
As I have stated throughout the paper, there needs to be more research done on the long-term sequala of treatment of CPP with a GnRHa. Very few studies have been performed to look at long-term spatial memory and the link to PCOS. In order to usher a change in medicine more research must be completed on these subjects and show similar effects as time continues. While we must consider ethics, we must also find a way to be able to research this topic on human subjects.
In summation, the gold standard treatment for CPP is a GnRHa. While the current thought process in medicine is that GnRHa’s have no harmful long-term sequela, a new body of literature has shown otherwise. New links between GnRHa’s with the etiology of PCOS and metabolic dysfunction have been found. Due to many of these studies being the first of their kind, it is evident that more research needs to be done prior to proving this and changing the ways in which providers approach treatment of CPP. Without further literature and evidence, it is not possible to come to a definitive conclusion.
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