Triptorelin-Induced Delayed Transient Arterial Hypertension: A Case Series with Review of Literature

Anna Jolanda Gortan; Francesca Franco; Federica Rodofile; Paola Cogo

doi:10.4103/ipcares.ipcares_22_23

CASE SERIES WITH REVIEW OF LITERATURE

Year : 2023 | Volume : 3 | Issue : 2 | Page : 68-71

Triptorelin-Induced Delayed Transient Arterial Hypertension: A Case Series with Review of Literature

Anna Jolanda Gortan, Francesca Franco, Federica Rodofile, Paola Cogo
Department of Medicine, Division of Pediatrics, University of Udine, Udine, Italy

Date of Submission	23-Jan-2023
Date of Decision	28-Mar-2023
Date of Acceptance	25-Apr-2023
Date of Web Publication	24-May-2023

Correspondence Address:
Dr. Francesca Franco
Piazzale Santa Maria Della Misericordia, 15, Udine 33100
Italy

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_22_23

Abstract

Background: Gonadotropin-releasing hormone analogs (GnRHas) such as triptorelin have been found to be effective and safe in the suppression of central precocious puberty (CPP). Only minor and transient side effects have been reported with depot preparation used in children. Clinical Description: We present three children with CPP who developed late onset hypertension 18–24 months after starting triptorelin, a long-acting GnRHa depot preparation. The secondary causes of hypertension were ruled out on the basis of clinical findings, appropriate blood tests, echocardiography, and abdominal ultrasound. Management and Outcome: After starting therapy with GnRHa, the children were evaluated routinely every 2–3 months for the 1^st year, then every 6 months. They developed hypertension between 18 and 24 months after starting triptorelin. While therapy with triptorelin was stopped in all three children, only one of them was prescribed antihypertensive drug. The hypertension resolved gradually after discontinuation of triptorelin in all the children and antihypertensive was also omitted in the single case. Conclusion: Hypertension may be an adverse effect of triptorelin therapy and thus regular monitoring of blood pressure in children undergoing therapy with this drug for CPP is warranted.

Keywords: Blood pressure, central precocious puberty, follow-up, gonadotropin-releasing hormone analogs, pediatric

How to cite this article:
Gortan AJ, Franco F, Rodofile F, Cogo P. Triptorelin-Induced Delayed Transient Arterial Hypertension: A Case Series with Review of Literature. Indian Pediatr Case Rep 2023;3:68-71

How to cite this URL:
Gortan AJ, Franco F, Rodofile F, Cogo P. Triptorelin-Induced Delayed Transient Arterial Hypertension: A Case Series with Review of Literature. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 6];3:68-71. Available from: http://www.ipcares.org/text.asp?2023/3/2/68/377511

Precocious puberty, defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys, is increasingly being seen and treated over the years. It has been stated that there is a global reduction of 3 months per decade in the reference age at pubertal onset, as measured by Thelarche. [1,2] In 80% of females, it is idiopathic. Diagnosis is primarily based on a full clinical history, pubertal rate of progression, clinical examination, bone age, pelvic ultrasound, and blood tests to evaluate gonadotropins and sex steroid hormone levels. Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for the diagnosis of central precocious puberty (CPP).^[1]

The treatment of CPP consists of intramuscular or subcutaneous injections of GnRH analogues (GnRHa) to cause the suppression of pituitary-gonadal axis, so as to slow down bone maturation and improve adult height.^[2] Hypertension is one of the rare side effects of this therapy, with only very few cases reported.^{[3],[4],[5],[6]}

We report three children who developed transient hypertension 18–24 months after starting triptorelin for precocious puberty. The three girls presented to our pediatric endocrine clinic between 2002 and 2011. They were otherwise healthy, born out of an uneventful pregnancy, vaginal delivery without postnatal complications. They presented with the development of secondary sexual characteristics before the age of 8 years, associated with accelerated growth velocity.

As a standard protocol, the initial evaluation included complete history and a careful analysis of vital signs, presence of dysmorphism, pubertal stage according to Tanner system, height, weight, growth velocity, and growth curve. We performed routine blood tests such as complete blood count, renal, liver and thyroid function tests, wrist and hand X-ray to assess bone age according to Greulich and Pyle standards, pelvic ultrasound to assess for uterus size and ovarian volume. Normal prepubertal uterus has a tubular shape of approximately 2.5–4 cm length, the endometrium is normally not visible and ovarian average volume is 1.2–2.3 cm³.^[7] Finally, to confirm CPP, GnRH stimulation test and a brain magnetic resonance imaging (MRI) was done. On confirmation of CPP, intramuscular triptorelin was started at the dose of 3.75 mg, every 28 days.

After starting therapy, children were evaluated every 2–3 months for the 1^st year, then every 6 months with the follow-up visit. Monitoring included evaluation of body weight, height, height growth velocity, tanner stage, and blood pressure (BP).

Case 1

Clinical Description

A 7-year and 4-month-old Italian girl was referred to the pediatric endocrinologist because of bilateral breast enlargement, which had started a year earlier, associated with an accelerated height growth velocity. She was breastfed for 6 months and then weaned gradually. She had a healthy diet and regular bladder-bowel habits. She was healthy without allergies or important past medical or surgical illness. Maternal menarche was reported at the age of 12 years.

On examination, body weight was 32.5 kg (+1.61 SDS for age), height 134 cm (+1.76 SDS for age), body mass index (BMI) was 18.1 kg/m² (+1.13 SDS above median for age), and the latest annual growth velocity was 8.1 cm/year. Her BP was 93/58 mmHg (50^th centile for sex, age, and height).^[8] Her clinical general examination was normal. As per tanner staging, she had attained B3PH1 without axillarche.

Management and Outcome

Routine blood tests such as complete blood count, renal, and liver function tests were within the normal limits. Her free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels were 11.2 pg/mL (8.9–17.6 pg/mL) and 2 μU/mL (0.6–4.5 μU/mL), respectively. Her wrist and hand X-ray were done to assess bone age. According to Greulich and Pyle standards, her bone age was 3 years older than her chronological age. Pelvic ultrasound was consistent with pubertal activation: antero-posterior uterine axis 38 mm, endometrial thickness not estimable, longitudinal right ovary diameter was 31 mm and left ovary 20 mm. GnRH stimulation test was done using gonadorelin diacetate tetrahydrate 65 μg (2 μg/kg). The result showed luteinizing hormone (LH) peak of 14.4 U/L and follicle-stimulating hormone (FSH) of 8 UI/L, LH/FSH >1, thereby confirming the diagnosis of CPP. MRI of the brain was normal.

The child was started on treatment with intramuscular triptorelin, at the dose mentioned above. After starting therapy, the child was evaluated every 2–3 months during the 1^st year, followed by every 6 months. Monitoring included evaluation of body weight, height, height velocity, tanner stage, and BP.

After 9 months of treatment, her Tanner stage was B2PH1 with soft breast gland and reduced uterine size on pelvic ultrasound. At a follow-up visit, 24 months from the beginning of treatment, increased BP (134/69 mmHg) was noted. BP Holter monitoring confirmed hypertension (mean 24 h BP values 149/95 mmHg, >95^th centile for sex, age and height.^[8] The causes of secondary hypertension were excluded^[6] [Table 1]. Hypertension was associated with frequent episodes of epistaxis, so she was started on nifedipine 20 mg/day. Her BP gradually normalized by 2 months. As she had reached acceptable chronological age for puberty, with a deceleration of bone maturation [Figure 1] and thus a better predicted final adult height, triptorelin therapy was stopped, after 3 months from the beginning of antihypertensive therapy. Two months later, antihypertensive therapy was also stopped and BP was maintained within the normal limits for sex and age, thereafter.

Figure 1: Case 1: X-ray on the left done before starting GnRha (bone age 10 years according to Greulich and Pyle at the chronological age of 7 years and 4 months old). X-ray on the right done at the end of the treatment (bone age 10–11.5 years, at the chronological age of 10 years and 10 months). GnRHa: Gonadotropin-releasing hormone analogs

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Table 1: Laboratory investigations and imaging studies done in the three cases to exclude causes of secondary hypertension in the children

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Case 2

Clinical Description

An 8-year, 6-month-old Romanian girl was evaluated for menarche. She was adopted at age of 7, so her previous medical information and family history were not available. Bilateral breast enlargement, pubic hair, apocrine sweating and leucorrhea had been noticed at least 6 months prior. Her body weight was 34.5 kg (+1.17 SDS), height 133 cm (+0.44 SDS), BMI 19.5 kg/m² (+1.27 SDS), latest annual growth velocity was 10 cm/year. Her BP was 97/60 (50^th centile for sex, age, and height).^[8] Her general examination was normal, except for the Tanner stage that was B4PH2.

Management and Outcome

As per standard protocol, routine blood tests such as complete blood count, renal, and liver function tests were done, which were within the normal limits. Her fT4 and TSH levels were 12.6 pg/mL (8.9–17.6 pg/mL) and 1.2 μU/mL (0.6–4.5 μU/mL), respectively. Pelvic ultrasound showed a longitudinal uterine diameter of 70 mm, anteroposterior axis 24 mm, endometrial thickness was 8.6 mm measured on luteal phase, longitudinal right ovary diameter was 23 mm and left ovary 20 mm. Bone age was 11 years and 6 months. The diagnosis of CPP was confirmed by GnRH test (LH peaked at 30 min: 4.3 U/L). MRI brain was normal. She was started on triptorelin on the same regime as Case 1.

After 1 year of treatment, her Tanner stage was B3PH3. Pelvic ultrasound showed reduction in uterine size (longitudinal diameter from 70 mm to 46 mm, anteroposterior axis from 24 mm to 18 mm) and endometrial thickness (0.99 mm) at pelvic ultrasound. After 21 months, high BP values were found (135/82 mmHg, >95^th centile for sex, age, and height)^[8] and confirmed by BP Holter monitoring (mean 24 h BP values 130/80 mmHg, >95^th centile for sex, age, and height). All laboratory tests and imaging studies [Table 1] were normal, so secondary hypertension was excluded.

In view of the chronological age reaching normal puberty and acceptable slowing down of bone age of the child, we decided to stop triptorelin therapy. BP values returned to normal limits for sex and age (105/61 mmHg, 50^th centile for sex, age, and height)^[8] after 3 months of cessation of triptorelin therapy.

Case 3

Clinical Description

A healthy 7-year, 8-month-old Italian-Cuban girl presented to our department for thelarche, pubarche, and accelerated height growth velocity. On evaluation, her body weight was 32.5 kg (+1.40 SDS), height 132.5 cm (+1.16 SDS), and BMI 18.5 kg/m² (+1.18 SDS). Her height growth velocity was 7.1 cm/year and her BP was 115/65 mmHg (<90^th centile for sex, age, and height). Her Tanner stage was B4PH4.

As in other two cases, her routine blood tests, including TSH and fT4 values, were within the normal limits. Bone age was 11 years. Pelvic ultrasound showed a longitudinal uterine diameter of 15 mm, anteroposterior axis 10 mm, longitudinal right ovary diameter was 18 mm and left ovary 17 mm. A GnRH stimulation test was done, confirming the diagnosis of CPP (LH - 8.5 U/L, FSH - 4.5 U/L, LH/FSH >1). MRI brain was within the normal limits. The child was thus started on treatment with triptorelin. The BP was checked at every evaluation and it was always <90^th percentile for sex, age and height.^[8] After 19 months of treatment, bone age was between 11 and 12 years old, and BP was 151/72 mmHg (>95^th centile for sex, age and height)^[8] without related symptoms, and hence not treated. BP Holter monitoring confirmed hypertension (mean 24 h BP values 145/79 mmHg, >95^th centile for sex, age and height). Clinical findings and relevant investigations were not consistent with other causes of secondary hypertension [Table 1].

Considering the child's age, bone age and the reduction in growth velocity, therapy with triptorelin was stopped. The BP of the child was checked every week and it reduced gradually without starting antihypertensive therapy. Six months after stopping GnRH treatment, the child had a BP within the normal range for age, sex and height (103/61 mmHg, 50th centile for sex, age and height as per AAP 2017).^[8]

Discussion with Review of Literature

GnRHa are the treatment of choice in CPP and they work by binding with the rceptor of GnRH. Following an initial phase of increasing LH and FSH secretion, prolonged exposure to GnRH results in the inhibition of gonadotropin secretion.^[9] In Europe, the approved drugs are leuprolide acetate and triptorelin. In the United States, subcutaneous (SQ) LA, and histrelin acetate SQ implant are also approved to treat CPP.^[2]

Children undergoing therapy with GnRHa need a regular follow-up to evaluate the efficacy of suppressive treatment. Therapy with GnRHa is generally safe with only transient side effects such as pain, bruising, rashes, subcutaneous nodules, headache, hot flashes, slipped capital epiphysis, or anaphylaxis.^[9],[10] Arterial hypertension is a rare side effect correlated with the use of GnRHa.^{[3],[4],[5],[6]}

The exact cause of hypertension due to triptorelin is not known. Animal studies suggested that hypoestrogenism causes hypertension, inducing a significant alteration in contractility of the vein modifying venous capacitance function, distensibility, and changing the smooth muscle contractility of resistance arteries.^[11] These effects have a potential role in the development of hypertension after treatment with triptorelin both in adults and in children.^[12] In all the three cases described above, there was no evidence of development of obesity as a consequence of GnRHa treatment, eliminating the possibility of triptorelin-induced obesity causing hypertension.^[11]

Most of the cases available in the literature have reported arterial hypertension between 2 and 18 months after introduction of GnRHa.^{[3],[4],[5],[6]} An overview of the few cases reported in literature is depicted in [Table 2]. In our cases, hypertension developed between 18 and 24 months after starting long-acting depot therapy. As the initial BP values and those recorded 3–6 months after initiating therapy were recorded within normal limits, along with exclusion of other causes of secondary hypertension, late onset arterial hypertension following GnRHa therapy was considered as the most likely diagnosis. Only one patient was treated with antihypertensive drugs. Most of the common causes of secondary hypertension were excluded in our patients, and there were no signs of hypertensive complications. After discontinuation of therapy, BP normalized in 3–6 months, as in other cases reported in literature.^{[3],[4],[5],[6]}

Table 2: Review of literature showing case reports of hypertension during treatment with gonadotropin-releasing hormone analogs

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To conclude, late-onset arterial hypertension is an important but rare complication of GnRHa therapy. The condition can be identified by regular monitoring and follow-up especially after 18 months of treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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