Functional Amenorrhea and Pituitary Microadenoma

1 IIIrd Department of General Surgery and Emergency, Emergency University Hospital, Bucharest, Romania 2 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 County Clinical Hospital, Cluj-Napoca, Romania 4 Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania 5 „C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania 6 „Iuliu Hatieganu” University of Medicine and Pharmacy & County Clinical Hospital, Cluj-Napoca, Romania 7 „Sf. Pantelimon” Clinical Emergency Hospital, Bucharest, Romania Corresponding author: Mara CARSOTE, „C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania. E-mail: carsote_m@hotmail.com Abstract

amenorrhea may be the most obvious clinical abnormality 7 .

CASE REPORT
A 27-year-old female without signifi cant medical history was admitted for evaluation due to the absence of menstrual cycles for more than 18 months, insomnia, polydipsia (around 4-6 l water intake/day) and polyuria. Clinical examination revealed weight of 42 kg, height of 167 cm, BMI (Body Mass Index) of 17.5 kg/ m 2 , normal blood pressure of 110/65 mmHg, heart rate of 74bpm, normal secondary sex characteristics, pallor of the skin and mucosa. Th e hormonal profi le showed normal FSH (Follicle Stimulating Hormone) levels, low LH -Luteinizing Hormone (of 0.15 U/L, normal: 1.20-12.8 U/L), estradiol (of 11.2 pg/mL, normal: 49-291 pg/mL) and progesterone (of 1.13 ng/mL, normal: 5.16-18.56 ng/mL). No pathological changes were recorded at somatotropic, lactotropic, thyrotropic and corticotropic levels ( Table 1). Diphereline (Triptorelin) stimulation test was performed: FSH, LH and estradiol were measured after administration of 0.1 mg dipherelines ©, at baseline, 4 hours and 24 hours, respectively. Increased levels of FSH and LH 4 hours after diphereline, as well as the adequate increase of es-

INTRODUCTION
FHA is one of the most common causes of secondary amenorrhea, classifi ed as hypogonadotropic hypogonadism due to an alteration of the pulsatile release of gonadotropin-releasinghormone (GnRH) from the hypothalamus [1][2][3] . Disturbances in the hypothalamic-pituitary-ovarian axis may include a lower mean frequency of LH pulses, the complete absence of LH pulsatility, as well as a normal-appearing secretion pattern and higher mean frequency of LH pulses 4 . Consequently, production of estrogen in the ovary will be reduced. Depending on the causative factor, FHA is divided into three categories: weight loss-related, exercise-related and stress-related 5 . Secondary amenorrhea, defi ned as the absence of menses for 3 or more months, occurs in approximately 3-5% of adult women. According to the American Society of Reproductive Medicine, FHA is responsible for 20-35% of secondary amenorrhea cases and approximately 3% of primary amenorrhea cases 6 . Although the exact risk is unknown, patients with menstrual irregularity or secondary amenorrhea are at risk of hyperprolactinemia and pituitary adenomas. Pituitary adenomas may present during puberty in association with delayed or incomplete development of secondary sex characteristics. Primary or secondary normale de FSH (hormon foliculostimulant), LH scăzut -hormon luteinizant (de 0,15 U / L, normal: 1,20-12,8 U / L), estradiol (de 11,2 pg / mL, normal: 49-291 pg / mL) și progesteron (de 1,13 ng / mL, normal: 5,16-18,56 ng / mL). Nu s-au înregistrat modifi cări patologice la niveluri somatotrope, lactotrope, tirotrope și corticotrope. Testul de stimulare cu diphereline a relevat integritatea funcţională a glandei hipofi zare și a ovarelor. Testarea progesteronului a fost negativă. Nu au existat rezultate patologice privind testările biochimice și testul de deprivare a apei a exclus diabetul insipid. Explorarea morfologică a regiunii hipotalamice-hipofi zare prin scanarea RMN (rezonanţă magnetică nucleară) îmbunătăţită prin contrast a scos la iveală un microadenom hipofi zar stâng cu un diametru de 5 mm. S-au recomandat măsuri dietetice şi un tratament contraceptiv oral adecvat. Concluzie: Amenoreea hipotalamică funcţională este cauza cea mai frecventă a amenoreei neuroendocrine. Identifi carea contextului și a factorilor cauzali este esenţială pentru luarea unei decizii terapeutice adecvate. Cuvinte cheie: amenoree, polidipsie, diphereline. tradiol levels after 24 hours confi rmed the functional integrity of the pituitary and ovaries ( Table 2). Pelvic ultrasound revealed a linear endometrium of approximately 3 mm, without pathological changes in ovarian morphology. Th e water deprivation test, carried out over a period of 6 hours, excluded diabetes insipidus. Th ere were no pathological fi ndings on biochemical workup. Morphological exploration of the hypothalamic-pituitary region by contrast-enhanced MRI showed a left pituitary microadenoma measuring 5 mm in diameter. Because no withdrawal bleeding appeared after oral progesterone administration, oral contraceptive treatment was initiated. Adequate diet was also recommended.

DISCUSSIONS
Functional hypothalamic amenorrhea should be diff erentiated from other forms of primary or secondary amenorrhea. In this case, the discovery of a pituitary adenoma on MRI raised the suspicion of hypogonadotropic hypogonadism caused by the pituitary tumor. At fi rst sight, the presence of a polyuro-polydipsic syndrome was an argument in favor of a possible link between the adenoma and secondary amenorrhea.
Th e primary approach in determining the cause of secondary amenorrhea is the assessment of gonadotropin levels and identifying hypogonadotropic hypogonadism 8 . Th e diphereline test is a keytool in the diagnosis of FHA, showing a positive response of gonadotropins to exogenous GnRH stimulation. Th is test distinguishes between hypothalamic dysfunction and primary pituitary diseases, also characterized by hypogonadism 9 .
In this case the levels of FSH, LH and estradiol before and after diphereline administration were highly suggestive for FHA.Th e patient's history also advocates in favor of FHA: menarche occurred spontaneously at the age of 12, she had regular menstrual cycles up until the past 18 months, amenorrhea occurred in the context of weight loss, accompanied by repeated episodes of insomnia. Th e polyuro-polydipsic syndrome was also interpreted as a reaction to stress after the water restriction test excluded diabetes insipidus.
FHA should not be considered only as a symptom, such as amenorrhea. Th is disorder has a more profound clinical picture [3][4][5] . Th e fi nal endocrine consequence of GnRH and gonadotropin pulsatile secretion impairment is profound hypoestrogenism. Hypoestrogenic status has a negative impact on diff erent aspects of female health, not just in menopausal women but also in younger ones [3][4][5] . Normal estrogen levels and metabolic homeostasis have a major importance for the cardiovascular system, normal bone metabolism and mental health, especially in younger women [10][11][12][13][14] . Th erefore, prolonged hypoestrogenism that occurs in young women may have critical signifi cance in the years to come. For this reason, in our patient's case we decided to initiate oral contraceptives. At the same time, we recommended limiting water intake, avoiding stressful situations and adequate food intake in order to reach a normal BMI. Periodic monitoring of the pituitary adenoma is required.
Pitutary incidentaloma is most frequently an incidental fi nding without a pattern related to age [15][16][17] . Whether in this case it might represent a hallmark of a genetic late onset central hypogonadism is still challenging to confi rm at this point.

CONCLUSION
Functional hypothalamic amenorrhea is an underestimated clinical problem. FHA patients should be carefully diagnosed and appropriately treated in order to prevent both short-term and, particularly, long-term medical consequences.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study.