Kasus20-2010-Seorang Wanita Berumur 32 Tahun dengan Oligomenoredan Infertilitas PresentasiKasus Dr ElizabethGuancial(Dokter): Seorang wanita berumur 32 tahun yang dievaluasi karenaoligomenoredan kesulitanhamil. Menarche terjadi saat berumur 12 tahun dan menstruasinya teratur sampai pasien mulai menggunakan kontrasepsi oral pada umur 20 tahun.Pada usia 25 tahun, dia menghentikan kontrasepsi oral dan siklus haidnya menjadi tidak teratur, antara 31-51 hari, dengan aliran menstruasi yang berdurasi selama 7 hari. Antara usia 28 dan 32 tahun, ia koitus tanpa kondom dengan suaminya tetapi tidak hamil. Pada usia 32 tahun, penyedia layanan kesehatan primer merujuknya kedokter ginekologist karena infertilitas. Pasien melaporkan bahwa pengujian dengan over-the-counter ovulasi prediktor-kit tidak menunjukkan bukti ovulasi. Pemeriksaan panggul tidak menunjukkan ada kelainan. Klomifen sitrat diberikan(100mg pada hari ke 5sampai 9dari siklushaid). Hasil uji laboratorium ditunjukkan dalam Tabel1. Tabel 1. Hasil Pengujian Laboratorium..Sebuah histerosalpingogram normal.
Dua bulan kemudian, pasien terlihat di klinik endokrin reproduksi pada rumah sakit lain. Dia melaporkan jerawat dan rambut wajah yang sering dia buang secara manual. Dia tidak merasakan sakit pada saat menstruasi dan tidak ada perdarahan intermenstrual. Papsmear normal, dan tidak ada riwayat penyakit menular seksual, penggunaan perangkat 1
intrauterin, atau paparan terhadap dietilstilbestrol. Pengobatan satu – satunyaadalahvitamin prenatal dan folat, dan hasil elektro foresis hemoglobin dan tesskrining fibrosis kistik telah dilaporkan normal. Klomifensitrat(150mg) diberikan (pada hari 5 sampai 9 dari siklus). Ultrasonografi panggul mengungkapkan bahwa endometrium adalah 8,8mm tebal dan homogenechogenic; bahan cairan dan echogenic yang dianggap darah berada dalam rongga, dan5 sampai 10 kista sederhana (fungsional krista) berada diovarium kanan. Hasil laboratorium uji ditunjukkan dalamTabel 1. Satu bulan kemudian, tingkat serum HCG meningkat; USG menunjukkan janin intrauterin tunggal. Hasil tes laboratorium rutin normal. Kehamilan itu dipersulit dengan diabetes mellitus gestasional, dengan dietterkontrol. Setelah usia kehamilan 40 minggu, pasien melahirkan bayi sehat dengan cara persalinan pervaginam spontan. Dia memberi ASI anaknya selama 12 bulan dan memiliki satu episode spontan dari aliran menstruasi selama waktu itu. Intoleransi glukosa menetap, tapi ia menolak pengobatan. Dia sering sakit kepala, hal ini dihubungkan dengan sinusitis. Ketika pasien berusia 34 tahun, CT-scan dari sinus, dilakukan karena sakit kepala frontal menetap dan nasal discharge, menunjukkan ada lesi di daerah sella. MRI yang dilakukan 11 hari kemudian menunjukan lesi (gambaran sebesar 2,8cm x2,4 x cm2,4cm dan isointense terhadap materi abu-abu pada T1-weighted dan T2-weighted) yang telah meluas ke wilayah suprasellar dan berbatasan dengan kiasmeoptik, dengan kompresi ringan dan kemungkinan invasi ke sinus kavernosa kanan. Dengan pemberian bahan kontras, peningkatan merata yang ringan tampak jelas.Tengkorak adalah menebal secara difus, dan sinus frontal yang menonjol. Hasil tes laboratorium ditunjukkan pada Tabel1. Pasien dirujukke klinik Neuro endocrinology pada rumah sakit ini. Pasien melaporkan penurunan libido setelah menghentikan kontrasepsi oral, hot flashesin termiten disertai dengan jantung berdebar, dan amenore selama hampir 1 tahun. Dia sesekali "floaters" dalam penglihatannya tapi tidak kehilangan penglihatan perifer. Dia mengalami nyeri kronis dan kekakuan pada lutut, bahu, dan tangan, serta mati rasa an kesemutan sesekali di tangan, yang telah terjadi selama kurang lebih 13 tahun. Selama periode yang sama, semakin banyak rambut gelap kasar tumbuh di wajahnya; penggelapan kulit dari bagian belakang leher, ketiak, dan selangkangan terjadi; berat badannya meningkat18,1kg; dan mendengkur, kelelahan, dan mengantuk siang hari sesekali, timbul perasaan susah bernapas saat tidur.Ukuran sepatunya telah meningkat dari ukuran7 (ukuran Eropa38) menengah untuk ukuran 8 (ukuran Eropa39) ganda-lebar, ukuran cincinnya juga meningkat, dan dia berpikir bahwa hidungnya telah menjadi lebih besar. Dia tidak memiliki rasa sakit perut, mual, muntah, diare, pusing, haus nyeri dada, gangguan pernafasan, edema perifer, rasa haus atau kelaparan yang berlebihan atau poliuria. Sekitar 2 tahun sebelumnya, selama kehamilannya, sakit kepala yang tajam, terkait dengan perubahan visual, telah muncul selama di pesawat udara ke kota lain. CT scan otak di rumah sakit setempat dilaporkan menunjukkan bukti sinusitis frontal kiri. Setelah menerima laporan dari CT normal tak lama sebelum evaluasi ini, ia menghubungi fasilitas lainnya dan diberitahu bahwa laporan CT sebelumnya telah dijelaskan perluasan sela tursika.
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Untuk2 tahun sebelumnya, pasien sudah mengalami episode intermiten sinusitis akut, di obati dengan antibiotik dan semprot hidung, dan alergi lingkungan musiman; kutil plantar telah dipotong, dan gigi bungsu telah diambil di masa lalu. Dia tinggal bersama suami dan bayi, bekerja di bidang akademik, minum alkohol jarang, dan tidak merokok atau menggunakan obat-obatan terlarang. Dia keturunan kulit putih dan Asia. Ibunya memiliki kolesterol tinggi dan osteoporosis; ayahnya adalah obesitas, dengan edema perifer dan hipertrofi prostat, dan seorang bibi ibu menderita diabetes mellitus tipe2. Termasuk obat vitamin, kalsium, minyak n-3ikan, tretinoin topikal, benzoyl peroxide, dan loratadine sesuai kebutuhan. Dia tidak punya alergi diketahui obat. Tanda-tanda vital normal. Berat badan adalah74, 8kg, tinggi 162, 6cm, dan indeks massa tubuh (berat dalam kilogram dibagi dengan kuadrat tinggi dalam meter) 29,2. Wajah dan hidung yang luas, alis itu menonjol, dan gigi dan rahang mengungkapkan underbite sedikit; adama croglossia tidak. Ada jerawat wajah, tag kulit ganda, dan acanthosis nigricans. Tangan besar-besar, dan jari-jari tebal. Sisa dari pemeriksaan tersebut normal. Sebuah tes diagnostik dilakukan. DiferensialDiagnosis Dr AndreaL.Utz: Wanita ini dipresentasikan pada 32 tahun dengan kondisi yang sangat umum oligomenore berselang. Diagnosis diferensial untuk oligomenore dan amenore sekunder adalah luas dan termasuk penyebab fisiologis, seperti kehamilan, menyusui, dan menopause; penyebab anatomi, seperti sindrom Asherman(diakui sisi adhesi intrauterine), dan beberapa penyebab anovulasi. Pasien ini memiliki bukti anovulasi. Anovulasi Anovulasi bisa disebabkan oleh salah satu gangguan ovarium atau disregulasi dari keberputaran sekresi gonadotropin. Disfungsi ovarium paling sering karena kerusakan autoimun dari ovarium, agen kemoterapi, radiasi panggul, atau kelainan genetik (misalnya, sindrom Turner atau premutations untuk sindrom X rapuh). Supresiatau gangguaniramapelepasan gonadotropindapat disebabkan olehlesihipotalamus, lesi dari infun di bulu mata uhipofisis atau kedua kekurangan gizi, atau pengeluaran energi yang berlebihan, disfungsi hormonal lainnya (misalnya, hiperprolaktinemia, disfungsi tiroid, hypercortisolemia, atau hormon pertumbuhan berlebih), adrenal atau ovarium neoplasma atau hiperplasia, penyebab iatrogenik (misalnya, penggunaan estrogen, progestin, androgen, atau opiat), dan ovarium polikistik syndrome. Polycystic Ovarium Syndrome Kriteria yang telah diusulkan untuk menegakkan diagnosa dari sindrom ovarium polikistik meliputi oligo-ovulasi atau anovulasi, bukti biokimia atau bukti klinis (misalnya, hirsutisme, jerawat, atau laki-laki-pola alopecia) dari hiperandrogenisme, ovarium polikistik pada USG, dan tidak adanya penyebab lain dari gangguan hormonal. Konsensus kelompok terus memperdebatkan kriteria khusus yang diperlukan untuk menentukan ovarium polikistik syndrome. Gangguan yang dapat meniru sindrom ovarium polikistik termasuk hiperplasia 3
adrenal kongenital nonclassic, hiperprolaktinemia, sindrom Cushing, akromegali, mensekresi androgen tumor pada kelenjar adrenal atau ovarium , sindrom resistensi insulin parah, dan beberapa obat (misalnya, asam valproik dan androgen) .5 Pasien ini memiliki oligomenore intermiten, dan secara klinis dia memiliki gejala hiperandrogenisme ringan. Pemeriksaan USG ovarium mengungkapkan 5 sampai 10 kista sederhana pada satu ovarium, yang tidak memenuhi kriteria Rotterdam untuk ovarium polikistik (setidaknya satu ovarium dengan lebih dari 12 folikel berukuran 2 hingga 9 mm). Penyebab Infertilitas Selain - dan mungkin berhubungan dengan - ketidakteraturan menstruasi, pasien ini juga memiliki infertilitas. Bagi pasangan, penyebab utama infertilitas kelainan anatomi perempuan, disfungsi ovulasi, infertilitas dijelaskan atau idiopatik, dan faktor infertility. Analisis semen laki-laki adalah langkah awal dalam evaluasi infertilitas pria, dan jika kelainan ini ditemukan, pengujian lebih lanjut dari testosteron dan gonadotropin adalah indicated. Evaluasi Infertilitas pada Wanita Metode penilaian infertilitas wanita adalah sama dengan menilai oligomenore tapi juga meliputi beberapa tes tambahan. Evaluasi pasien harus menetapkan panjang dari siklus menstruasi; sejarah kehamilan, dan sejarah penyakit menular seksual, obat-obatan, perubahan berat badan, dan olahraga. Tes laboratorium awal umumnya mencakup pengukuran kadar human chorionic gonadotropin (hCG), thyrotropin, prolaktin, hari 3 follicle-stimulating hormone (FSH) dan estradiol, dan dehydroepiandrosterone sulfate (DHEAS), serta testosteron bebas (diukur melalui suatu akurat assay). Menstruasi teratur dalam siklus 21untuk-35-hari sering menyarankan siklus ovulasi. Pengukuran suhu tubuh basal dan ovulasi prediktor-rumah kit dapat membantu menilai waktu ovulasi. Ovulasi dapat dikonfirmasikan dengan mengukur tingkat progesteron selama fase midluteal. Histerosalpingografi dilakukan untuk menilai patensi dari saluran tuba serta setiap kelainan struktur rahim. Penilaian lain yang dipertimbangkan dalam evaluasi adalah tantangan, clomiphene folikel-fase ovarium ultrasonografi untuk penilaian folikel antral, dan laparoskopi dalam beberapa kasus endometriosis. Pasien ini memiliki tingkat normal thyrotropin, prolaktin, testosteron, dan DHEAS, tingkat hCG tidak diukur. Tingkat progesteron faseluteal adalah1,3ng permililiter (4,1nmolper liter) (nilai> 6 ngper mililiter[19,1 nmolper liter]dapat menandakan ovulasi). Depan ovulasi prediktor-kit tidak menunjukkan kenaikan tingkat hormon luteinizing (LH). Tingkat insulin puasa masih dalam batas normal, tetapi pada sisi yang tinggi bagi seorang wanita, muda mungkin sehat, tidak ada nilai glukosa diberikan untuk memperkirakan resistensi insulin. Tantangan Clomiphene menunjukkan tingkat FSH rendah normal dan kadar estradiol yang rendah pada awal dan pada hari10. Pasien tidak memiliki riwayat sugestif gizi buruk atau berolahraga. Histerosalpingogram adalah normal, dan endometrium tidak atrofi. Hasil ini sugestif kelainan hipofisis yang FSH produksi kecacatan dan mencegah stimulasi produksi estradiol, menandakan hipogonadisme hipogonadotropik mungkin. Hipofisis MRI adalah 4
tepat jika hipogonadisme hipogonadotropik dicurigai dan akan menjadi tepat pada waktu untuk pasien ini. Pasien secara spontan menjadi hamil setelah 4 tahun infertilitas. Selama kehamilan, gestational diabetes dikembangkan, dan diaterus memiliki toleransi glukosa setelah melahirkan. Dia diberi ASI secara normal, yang merupakan indikasi produksi prolaktinyang memadai. Tidak sampai dia disajikan dengan sakit kepala persisten dan nasal discharge bahwa diagnosis dari lesi hipofisis dibuat dengan penggunaan pencitraan. Lesi itu besar, dengan invasi guasinus dan kontak dengan kiasmeoptik; sella diperluas, dan calvarium itu difus mengental. Fitur-fitur ini menunjukkan bahwa lesi telah hadir untuk perpanjangan waktu. Bahkan, CT kepala dilakukan 2 tahun sebelumnya karena sakit kepala dilaporkan mengungkapkan sella hipofisis diperluas. Lesi Hipofisis Diagnosis banding lesi massa di hipofisis cukup luas dan dapat dibagi menjadi beberapa kategori utama: neoplasma, kista, hiperplasia, lesi inflamasi atau infiltratif, kondisi infeksi, dan lesi vaskular. Kelainan yang paling umum dalam sella hipofisis adalah adenoma jinak. Sebuah kista jinak, seperti kista sumbing Rathke, craniopharyngioma, meningioma, germinoma, atau metastasis juga harus dipertimbangkan. Hypophysitis dapat meniru lesi neoplastik pada scan MRI, seperti dapat sarkoidosis dan histiocytosis. Lesi pembuluh darah, seperti aneurisma dari segmen gua dari arteri karotis, jarang terjadi tetapi harus considered. Dr Pamela W. Schaefer: MRI scan T1-weighted dan T2-tertimbang tanpa bahan kontras mengungkapkan massa berpusat di sella yang isointense ke otak parenkim, dengan ekstensi ke dalam sumur suprasellar (Gambar 1 1Figure Scan MRI Daerah Sellar. ). Sella ini melebar dan direnovasi tanpa kerusakan tulang yang pasti. Ada massa berpengaruh pada kiasme optik, dan massa dapat menyerang sinus kavernosa yang tepat tanpa mempersempit kekosongan arteri karotid kanan aliran internal. Gradient-echo gambar tidak menunjukkan bukti perdarahan dalam gumpalan itu. Setelah administrasi gadolinium, ada ringan, peningkatan merata. Tangkai hipofisis dikaburkan oleh massa. Tengkorak adalah difus menebal dan sinus frontal yang menonjol.
Figure 1. MRI Scans of the Sellar Region
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Fitur dari massa muncul jinak dan yang paling konsisten dengan adenoma hipofisis. Craniofaringioma juga massa jinak, tetapi mereka biasanya muncul di wilayah suprasellar dan memperluas ke dalam sella tersebut. Mereka juga sering memiliki kista dan kalsifikasi dan biasanya terjadi pada anak dan 50-untuk-60-year-olds. Kista sumbing Rathke bersifat jinak dan biasanya timbul dalam sella, tetapi mereka biasanya tidak meningkatkan. Lesi ganas seperti limfoma dan metastasis biasanya lebih heterogen dan kurang dibatasi, dan mereka menghancurkan daripada tulang merombak. Granulomatosa proses dan kondisi infeksi dan inflamasi lainnya biasanya lebih infiltratif dan ini sering berhubungan dengan peningkatan meningeal basilar. Singkatnya, massa kemungkinan besar adenoma. Tengkorak menebal dan sinus frontal yang menonjol memberikan petunjuk untuk jenis tertentu adenoma. Dr Utz: Berdasarkan scan pencitraan, diagnosis yang paling mungkin adalah adenoma hipofisis. Untuk setiap lesi hipofisis, penting untuk mengevaluasi untuk disfungsi neurologis visual atau lainnya dari efek massa, untuk hypopituitarism dari gangguan fungsi hipofisis normal, dan untuk sindrom yang berhubungan dengan kelebihan hormon hipofisis. Hypopituitarism Menilai untuk hypopituitarism termasuk konfirmasi dari tingkat normal kortisol (tingkat kortisol acak atau kortikotropin-dirangsang> 18 mg per desiliter [500 nmol per liter]), hormon tiroid (tiroksin tingkat normal bebas), steroid gonad (menstruasi teratur pada wanita premenopause atau tingkat testosteron normal pagi pada pria), dan hormon pertumbuhan (hasil normal dari pengujian stimulasi hormon pertumbuhan). Diabetes insipidus jarang disebabkan oleh adenoma hipofisis, tetapi dengan lesi hipofisis lainnya dan sejarah klinis sugestif, cairan-kekurangan pengujian ditunjukkan. Syndrome Kelebihan Hormon Hipofisis Atas dasar sel asal mereka, adenoma hipofisis dibagi lagi menjadi Prolaktinoma, somatotroph adenoma (akromegali), corticotroph adenoma (penyakit Cushing), Thyrotropinmensekresi adenoma, dan adenoma hormon nonfunctioning biasanya berasal dari sel gonadotroph. Sebuah elevasi substansial dalam tingkat prolaktin biasanya menunjukkan bahwa lesi adalah prolaktinoma. Sebuah elevasi ringan pada tingkat prolaktin tidak selalu menunjukkan prolaktinoma dan mungkin akibat dari gangguan dari sinyal dopamin penghambatan dari hipotalamus (yang dikenal sebagai efek tangkai) oleh setiap gangguan yang mempengaruhi wilayah hipofisis, alternatif, obat-obat tertentu dapat menyebabkan peningkatan kadar prolaktin. Sindrom Cushing didiagnosis berdasarkan peningkatan kadar 24-jam kortisol urin, malam kortisol saliva, dan deksametason-ditekan kortisol serum. Setelah penentuan ketergantungan kortikotropin dan putusan itu keluar dari sumber ektopik sindrom kortikotropin pituitary mengkonfirmasi Cushing. Temuan tingkat serum insulin-seperti faktor pertumbuhan 1 (IGF-1) adalah sugestif dari akromegali, dan diagnosis dikonfirmasi oleh kurangnya penekanan hormon pertumbuhan 6
setelah pengujian penekanan glukosa oral. Thyrotropin-mensekresi adenoma menyebabkan peningkatan kadar tiroksin bebas dan nonsuppressed tingkat thyrotropin. Acromegaly Acromegaly, yang saya yakin pasien ini memiliki, adalah karena kelebihan produksi hormon pertumbuhan. Mengikat hormon pertumbuhan pada reseptor hepatik menyebabkan pelepasan sistemik IGF-1. Hormon pertumbuhan dan IGF-1 memiliki efek pada banyak jaringan, keseimbangan cairan, dan homeostasis glukosa. Diagnosis harus dipertimbangkan pada pasien dengan temuan klinis seperti prognatisme, Komandoisme frontal, lipatan nasolabial dalam, tengkorak menebal, melebar jarak gigi, underbite, edema wajah, macroglossia, tangan dan kaki membesar, tag kulit, keringat yang berlebihan, jerawat, sakit kepala perawakan yang tinggi (dalam orang-orang di antaranya gangguan terjadi sebelum penyelesaian pubertas), hipogonadisme, resistensi insulin atau diabetes mellitus, hipertensi, sleep apnea, sindrom carpal tunnel, arthralgia, hipertrofi jantung atau disfungsi katup, dan usus besar polyps. Pasien ini memiliki fitur klinis banyak acromegaly: hipogonadisme, perubahan rangka, jerawat, intoleransi glukosa, apnea tidur, dan arthralgias. Ketidakteraturan menstruasi ini pasien bisa saja disebabkan oleh hipogonadisme hipogonadotropik karena gangguan LH normal dan pelepasan FSH oleh hipofisis atau tumor mass12 hormon pertumbuhan yang berlebihan, yang mungkin telah memicu sindrom ovarium polikistik-seperti negara anovulasi. Kelebihan hormon pertumbuhan meningkatkan resistensi insulin, mungkin karena efek langsung selular atau mobilisasi asam lemak bebas. Dalam sebuah penelitian terhadap 14 wanita dengan aktif akromegali, 50% memiliki ovarium polikistik pada USG dan 43% memenuhi kriteria Rotterdam untuk fenotip ovarium polikistik syndrome. Wanita dengan acromegaly sering memiliki tanda dan gejala hiperandrogenisme, dengan estrogen normal dan testosteron tingkat dan rendah hormon seks pengikat globulin level. Pertumbuhan hormon atau IGF-1 atau baik secara langsung dapat mempengaruhi fungsi ovarium, atau hormon pertumbuhan dapat menyebabkan perubahan ini tidak langsung melalui hyperinsulinemia. Pasien ini kemungkinan besar telah aktif acromegaly saat dia hamil, yang mungkin telah berkontribusi terhadap diabetes kehamilan nya , tetapi juga mungkin berkontribusi pada intoleransi glukosa dia terus. Pasien ini memiliki beberapa karakteristik yang bisa menyebabkan diagnosis awal acromegaly. Kehadiran pola hipogonadisme hipogonadotropik hormonal selama evaluasi infertilitas menunjukkan kebutuhan untuk hipofisis MRI. Nya oligo-ovulasi dan hiperandrogenisme klinis memenuhi kriteria untuk fenotip sindrom ovarium polikistik, dan dengan demikian kasus ini menyoroti kebutuhan untuk mempertimbangkan penyebab alternatif fenotip sindrom ovarium polikistik. Fitur klinisnya adalah sugestif dari akromegali, dan pengukuran tingkat IGF-1 serum untuk memeriksa kelebihan hormon pertumbuhan ditunjukkan, seperti tes untuk penekanan hormon pertumbuhan setelah beban glukosa oral. Tidak diobati acromegaly mengurangi kelangsungan hidup, terutama pada pasien dengan diabetes mellitus atau jantung disease. Pengobatan awal biasanya reseksi bedah, yang mungkin prosedur yang dilakukan dalam kasus ini. Seringkali, tumor sisa tetap setelah 7
operasi, dan manajemen medis diperlukan. Terapi medis yang utama adalah analog somatostatin, hormon pertumbuhan antagonis reseptor, agonis dopamin, atau kombinasi dari semuanya. Radiasi mungkin diperlukan dalam beberapa cases. Dr Nancy Lee Harris (Patologi): Semoga kita memiliki diagnosis mahasiswa kedokteran? Sebuah Harvard Medical Siswa: Kami pikir bahwa penyebab paling mungkin dari gejala wanita ini adalah hormon pertumbuhan yang mensekresi adenoma hipofisis, karena massa sela tursika dan fitur klinis akromegali. Dr Lisa B. Nachtigall (Neuroendocrinology): Kami berpikir bahwa pasien ini telah acromegaly disebabkan oleh macroadenoma hormon pertumbuhan hipofisis yang mensekresi. Hasil visual-bidang pengujian normal. Pengujian laboratorium menunjukkan bahwa IGF-1 tingkat yang sedikit lebih tinggi pada 574 ng per mililiter (kisaran referensi, 114-492). Tes glukosa toleransi oral untuk menekan hormon pertumbuhan yang abnormal adalah nyata: setelah beban 75-g glukosa, pertumbuhan nadir tingkat hormon adalah 72 ng per mililiter (normal, <1). Pengujian tambahan dilakukan untuk mengevaluasi fungsi lainnya hipofisis anterior, karena pada pasien dengan massa Sellar, kompresi dapat menyebabkan disfungsi dari setiap sumbu hormon hipofisis. Meskipun tingkat thyrotropin normal, tingkat tiroksin bebas rendah, sebuah fitur konsisten dengan hipotiroidisme pusat. Tingkat kortisol dirangsang normal. LH, FSH, dan tingkat estradiol yang rendah, fitur konsisten dengan hipogonadisme hipogonadotropik pusat. Tingkat hemoglobin terglikasi yang sedikit lebih tinggi, sebuah fitur sugestif dari disfungsi metabolik yang berhubungan dengan akromegali. Tingkat prolaktin sedikit ditinggikan (pengukuran dilakukan pada sampel diencerkan), yang bisa saja disebabkan oleh hormon prolaktin cosecretion dan pertumbuhan atau efek dari tangkai kompresi oleh tumor. Diagnosis pra operasi kami adalah akromegali, hipotiroidisme dengan pusat, dan hipogonadisme hipogonadotropik. Cadangan adrenal normal. Kami merekomendasikan reseksi transsphenoidal tumor, yang dilakukan. Diagnosa Klinis Acromegaly yang berhubungan dengan macroadenoma hipofisis yang mensekresi hormon pertumbuhan.
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Dr Andrea L. Utz yang Diagnosis Acromegaly karena macroadenoma hipofisis yang mensekresi hormon pertumbuhan. Patologis Diskusi Dr Matija Snuderl: Kami menerima tumor sebagai fragmen beberapa jaringan berukuran 2,0 oleh 1,5 oleh 0,4 cm agregat. Evaluasi mikroskopis (Gambar 2A dan gambar 2B, 2 Pemeriksaan patologis dari Spesimen Tumor hipofisis dari Reseksi transsphenoidal.) Menegaskan diagnosis dari adenoma hipofisis dengan pleomorfisme selular moderat. Studi imunohistokimia mengungkapkan bahwa sebagian besar sel tumor yang reaktif untuk hormon pertumbuhan manusia (Gambar 2C), beberapa sel tumor reaktif untuk prolaktin, dan sel tumor sesekali adalah reaktif untuk subunit alpha. Pewarnaan imunohistokimia untuk cytokeratin CAM 5.2 (Gambar 2D) mengungkapkan pola sitoplasma difus positif. Indeks proliferasi, dinilai dengan Ki67 immunostaining, kurang dari 1% (Gambar 2D, inset). Sebuah indeks proliferasi rendah dan menyebar dgn urat saraf CAM 5,2 pola pewarnaan berhubungan dengan rendahnya risiko recurrence.
Gambar 2. Pemeriksaan patologis dari Spesimen Tumor hipofisis dari Reseksi transsphenoidal. Dr Harris: Dr Nachtigall, akan Anda memberitahu kami bagaimana pasien sekarang ? Dr Nachtigall: Pada 6 minggu pasca operasi pasien tindak lanjut, sebuah MRI hipofisis scan menunjukkan tidak ada bukti tumor. Hasil visual-bidang tes tetap normal. Ada yang cepat berkurang atau resolusi dari tanda dan gejala akromegali, termasuk carpal tunnel syndrome, nyeri sendi dan kekakuan, mendengkur, berkeringat, jerawat, dan hirsutisme, dan cincin ukuran pasien dan ukuran sepatu menurun. Periode menstruasi teratur kembali. Kadar glukosa darah puasa normal. IGF-1 tingkat normal di 369 ng per mililiter. Namun, setelah tes 9
glukosa toleransi oral, tingkat hormon pertumbuhan tetap meningkat sebesar 2,5 ng per mililiter (normal, <1). Sisa dari fungsi hipofisis pasien kembali normal, begitu pula tingkat hemoglobin terglikasi. Karena tingkat hormon pertumbuhan nadir tinggi setelah tes glukosa toleransi oral, kami menyarankan agar dia mulai terapi medis dengan dosis rendah analog somatostatin. Sepuluh minggu pasca operasi, kami mulai nya pada tanggal 10 mg bulanan octreotide. Dia melanjutkan terapi ini sampai sekitar 7 bulan setelah operasi, ketika dia berharap untuk hamil lagi. MRI scan nya tetap jelas, dan bidang visualnya normal. Dia spontan dikandung hampir persis 1 tahun pasca operasi. IGF-1 tingkat dan hasil-fungsi tiroid, glukosa, dan visual-field tes tetap normal selama kehamilan, dan ia melahirkan bayi yang sehat. Delapan bulan kemudian, IGF-1 tingkat adalah 646 ng per mililiter, dan suntikan bulanan octreotide dilanjutkan. IGF-1 tingkat sekarang normal, dan 2,5 tahun setelah pengangkatan adenoma, pasien tetap baik. Anatomi Diagnosis Adenoma hipofisis dengan produksi hormon pertumbuhan. Kasus ini dipresentasikan pada Konferensi Kasus Medis, 12 Desember 2008. Pengungkapan bentuk yang disediakan oleh penulis yang tersedia dengan teks penuh artikel ini di NEJM.org. Kami berterima kasih kepada Dr Lisa B. Nachtigall untuk membantu mempersiapkan sejarah kasus dan untuk memberikan tindak lanjut informasi. Informasi Sumber Dari Unit neuroendokrin (ALU) dan Departemen Radiologi (PWS) dan Patologi (MS), Rumah Sakit Umum Massachusetts, dan Departemen Kedokteran (ALU), Radiologi (PWS), dan Patologi (MS), Harvard Medical School - keduanya di Boston, dan Pusat hipofisis, Vanderbilt University Medical Center di Nashville (ALU).
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Case Records of the Massachusetts General Hospital Richard C. Cabot, Founder, Nancy Lee Harris, M.D., Editor, Jo-Anne O. Shepard, M.D., Associate Editor, Eric S. Rosenberg, M.D., Associate Editor, Alice M. Cort, M.D., Associate Editor, Sally H. Ebeling, Assistant Editor, Christine C. Peters, Assistant Editor
Case 20-2010 — A 32-Year-Old Woman with Oligomenorrhea and Infertility Andrea L. Utz, M.D., Ph.D., Pamela W. Schaefer, M.D., and Matija Snuderl, M.D. N Engl J Med 2010; 363:178-186 July 8, 2010 Presentation of Case Dr. Elizabeth Guancial (Medicine): A 32-year-old woman was evaluated because of oligomenorrhea and difficulty becoming pregnant. Menarche had occurred at 12 years of age and menses were regular until the patient began taking oral contraceptives at 20 years of age. At 25 years of age, she discontinued oral contraceptives and irregular menstrual cycles developed, ranging from 31 to 51 days, with menstrual flow of 7 days' duration. Between the ages of 28 and 32 years, she had unprotected coitus with her husband but did not conceive. At 32 years of age, her primary care provider referred her to a gynecologist because of infertility. The patient reported that testing with over-the-counter ovulation-predictor kits did not show evidence of ovulation. Pelvic examination revealed no abnormalities. Clomiphene citrate was administered (100 mg on days 5 through 9 of the menstrual cycle). Laboratory-test results are shown in Table 1
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Table
1.
Results
of
Laboratory
Tests..
A
hysterosalpingogram
was
normal.
Two months later, the patient was seen in the reproductive endocrine clinic of another hospital. She reported frequent acne and facial hair that she removed manually. She had no pain with menstruation and no intermenstrual bleeding. Papanicolaou smears had been normal, and there was no history of sexually transmitted diseases, use of intrauterine devices, or exposure to diethylstilbestrol. Her only medications were prenatal vitamins and folate, and results of hemoglobin electrophoresis and cystic fibrosis screening tests had reportedly been normal. Clomiphene citrate (150 mg) was administered (on days 5 through 9 of the cycle). Ultrasonography of the pelvis revealed that the endometrium was 8.8 mm thick and homogeneously echogenic; fluid and echogenic material that was thought to be blood was present in the cavity, and 5 to 10 simple cysts were present in the right ovary. Laboratory-test results are shown in Table 1. One month later, the serum level of human chorionic gonadotropin was elevated; ultrasonography revealed a single intrauterine fetus. Routine laboratory-test results were normal. The pregnancy was complicated by gestational diabetes mellitus, which was dietcontrolled. After a 40-week gestation, the patient delivered a healthy infant by means of spontaneous vaginal delivery. She breast-fed her child for 12 months and had one spontaneous episode of menstrual flow during that time. Glucose intolerance persisted, but she declined treatment. She had frequent headaches, attributed to sinusitis.
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When the patient was 34 years of age, computed tomography (CT) of the sinuses, performed because of persistent frontal headaches and nasal discharge, revealed a lesion in the sella. Magnetic resonance imaging (MRI) performed 11 days later revealed a lesion (2.8 cm by 2.4 cm by 2.4 cm and isointense to gray matter on T1-weighted and T2-weighted images) that extended into the suprasellar region and abutted the optic chiasm, with mild compression and possible invasion of the right cavernous sinus. With the administration of contrast material, mild patchy enhancement was evident. The skull was diffusely thickened, and the frontal sinuses were prominent. Results of laboratory tests are shown in Table 1. The patient was referred to the neuroendocrinology clinic of this hospital. The patient reported decreased libido after stopping oral contraceptives, intermittent hot flashes accompanied by palpitations, and amenorrhea for almost 1 year. She had occasional “floaters” in her vision but no loss of peripheral vision. She had chronic pain and stiffness in the knees, shoulders, and hands, as well as occasional numbness and tingling in the hands, which had been occurring for approximately 13 years. During the same period, increasing numbers of coarse dark hairs grew on her face; darkening of the skin of the back of her neck, axilla, and groin occurred; her weight had increased 18.1 kg; and snoring, fatigue, and occasional daytime somnolence, suggestive of obstructive sleep apnea, developed. Her shoe size had increased from size 7 (European size 38) medium to size 8 (European size 39) double-wide, her ring size had also increased, and she thought that her nose had become larger. She did not have abdominal pain, nausea, vomiting, diarrhea, dizziness, chest pain, respiratory symptoms, peripheral edema, or excessive thirst or hunger or polyuria. Approximately 2 years earlier, during her pregnancy, a sharp headache, associated with visual changes, had developed during an airplane flight to another city. CT scans of the brain at a local hospital reportedly showed evidence of left frontal sinusitis. After receiving the report of the abnormal CT shortly before the present evaluation, she contacted the other facility and was told that the report of the earlier CT had described expansion of the sella turcica. For the previous 2 years, the patient had had intermittent episodes of acute sinusitis, treated with antibiotics and nasal spray, and seasonal environmental allergies; plantar warts had been excised, and wisdom teeth had been extracted in the past. She lived with her husband and baby, worked in academics, drank alcohol rarely, and did not smoke or use illicit drugs. She was of white and Asian ancestry. Her mother had high cholesterol and osteoporosis; her father was obese, with peripheral edema and prostatic hypertrophy; and a maternal aunt had diabetes mellitus type 2. Medications included vitamins, calcium, n−3 fish oil, topical tretinoin, benzoyl peroxide, and loratadine as needed. She had no known allergies to medications. The vital signs were normal. The weight was 74.8 kg, the height 162.6 cm, and the body-mass index (the weight in kilograms divided by the square of the height in meters) 29.2. The face and nose were broad, the brow was prominent, and the teeth and jaw revealed a slight underbite; there was no macroglossia. There was facial acne, multiple skin tags, and
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acanthosis nigricans. The hands were large, and the fingers were thick. The remainder of the examination was normal.
A diagnostic test was performed. Differential Diagnosis Dr. Andrea L. Utz: This woman presented at 32 years of age with the very common condition of intermittent oligomenorrhea. The differential diagnosis for secondary oligomenorrhea and amenorrhea is broad and includes physiological causes, such as pregnancy, lactation, and menopause; anatomical causes, such as Asherman's syndrome (acquired intrauterine adhesions); and multiple causes of anovulation. This patient had evidence of anovulation. Anovulation Anovulation may be caused by either ovarian impairment or dysregulation of the cyclicity of gonadotropin secretion. Ovarian dysfunction is most commonly due to autoimmune destruction of the ovary, chemotherapeutic agents, pelvic irradiation, or genetic abnormalities (e.g., Turner's syndrome or premutations for the fragile X syndrome). Suppression or disruption of the rhythm of gonadotropin release can be caused by lesions of the hypothalamus, lesions of the infundibulum or the pituitary or both, malnutrition or excessive energy expenditure, other hormonal dysfunction (e.g., hyperprolactinemia, thyroid dysfunction, hypercortisolemia, or growth hormone excess), adrenal or ovarian neoplasms or hyperplasia, iatrogenic causes (e.g., use of estrogens, progestins, androgens, or opiates), and the polycystic ovary syndrome.1 Polycystic Ovary Syndrome The criteria that have been proposed to establish a diagnosis of the polycystic ovary syndrome include oligo-ovulation or anovulation, biochemical evidence or clinical evidence (e.g., hirsutism, acne, or male-pattern alopecia) of hyperandrogenism, polycystic ovaries on ultrasonography,2 and the absence of other causes of hormonal disruption. Consensus groups continue to debate the specific criteria required to define the polycystic ovary syndrome.3,4 Disorders that can mimic the polycystic ovary syndrome include nonclassic congenital adrenal hyperplasia, hyperprolactinemia, Cushing's syndrome, acromegaly, androgensecreting tumors of the adrenal glands or ovary, syndromes of severe insulin resistance, and some medications (e.g., valproic acid and androgens).5 This patient had intermittent oligomenorrhea, and clinically she had mild hyperandrogenism symptoms. An ovarian ultrasound examination revealed 5 to 10 simple cysts on one ovary, which does not meet the Rotterdam criteria for polycystic ovaries (at least one ovary with more than 12 follicles measuring 2 to 9 mm in diameter). 14
Causes of Infertility In addition to — and probably related to — her menstrual irregularity, this patient also had infertility. For couples, the primary causes of infertility are female anatomical abnormalities, ovulatory dysfunction, unexplained or idiopathic infertility, and male factor infertility.6 Semen analysis is the initial step in the evaluation of male infertility, and if an abnormality is uncovered, further testing of testosterone and gonadotropins is indicated.7 Evaluation of Infertility in Women The method of assessing female infertility is similar to that of assessing oligomenorrhea but includes some additional tests. Evaluation of the patient should establish the length of the menstrual cycle; the gestational history; and the history of sexually transmitted diseases, medications, weight changes, and exercise. Initial laboratory tests generally include measurement of levels of human chorionic gonadotropin (hCG), thyrotropin, prolactin, day 3 follicle-stimulating hormone (FSH) and estradiol, and dehydroepiandrosterone sulfate (DHEAS), as well as free testosterone (measured by means of an accurate assay). Regular menses within a 21-to-35-day cycle often suggest ovulatory cycles. Measurement of basal body temperature and home ovulation-predictor kits can help assess the timing of ovulation. Ovulation can be confirmed by measuring the progesterone level during the midluteal phase. Hysterosalpingography is performed to assess the patency of the fallopian tubes as well as any structural abnormalities of the uterus. Other assessments considered in the evaluation are clomiphene challenge, follicular-phase ovarian ultrasonography for antral follicle assessment, and laparoscopy in some cases of endometriosis.8 This patient had normal levels of thyrotropin, prolactin, testosterone, and DHEAS; the hCG level was not measured. The luteal-phase progesterone level was 1.3 ng per milliliter (4.1 nmol per liter) (a value >6 ng per milliliter [19.1 nmol per liter] is suggestive of ovulation). Home ovulation-predictor kits did not show a rise in the level of luteinizing hormone (LH). A fasting insulin level was within the normal range but on the high side for a young, presumably healthy woman; no glucose value was provided to estimate insulin resistance. Clomiphene challenge showed low normal FSH levels and low estradiol levels at baseline and at day 10. The patient did not have a history suggestive of malnutrition or excessive exercise. The hysterosalpingogram was normal, and the endometrium was not atrophic. These results are suggestive of a pituitary abnormality that was impairing FSH production and preventing the stimulation of estradiol production, signifying possible hypogonadotropic hypogonadism. Pituitary MRI is appropriate if hypogonadotropic hypogonadism is suspected and would have been appropriate at that time for this patient. The patient spontaneously became pregnant after 4 years of infertility. During the pregnancy, gestational diabetes developed, and she continued to have impaired glucose tolerance after delivery. She breast-fed normally, which is an indication of adequate prolactin production. It was not until she presented with persistent headaches and nasal discharge that 15
the diagnosis of a pituitary lesion was made with the use of imaging. The lesion was large, with cavernous sinus invasion and contact with the optic chiasm; the sella was expanded; and the calvarium was diffusely thickened. These features suggest that the lesion had been present for an extended time. In fact, CT of the head performed 2 years earlier because of a headache reportedly revealed an expanded pituitary sella. Pituitary Lesions The differential diagnosis of a mass lesion in the pituitary is quite broad and can be broken down into several primary categories: neoplasms, cysts, hyperplasia, inflammatory or infiltrative lesions, infectious conditions, and vascular lesions. The most common abnormalities within the pituitary sella are benign adenomas. A benign cyst, such as Rathke's cleft cyst, craniopharyngioma, meningioma, germinoma, or metastasis must also be considered. Hypophysitis can mimic a neoplastic lesion on MRI scans, as can sarcoidosis and histiocytosis. Vascular lesions, such as aneurysms of the cavernous segment of the carotid artery, are rare but must be considered.9 Dr. Pamela W. Schaefer: T1-weighted and T2-weighted MRI scans without contrast material reveal a mass centered in the sella that is isointense to brain parenchyma, with extension into the suprasellar cistern (Figure 1). The sella is widened and remodeled without definite bone destruction. There is mass effect on the optic chiasm, and the mass may invade the right cavernous sinus without narrowing the right internal carotid artery flow void. Gradient-echo images show no evidence of hemorrhage within the mass. After the administration of gadolinium, there is mild, patchy enhancement. The pituitary stalk is obscured by the mass. The skull is diffusely thickened and the frontal sinuses are prominent.
.
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Figure 1. MRI Scans of the Sellar Region The features of the mass appear benign and are most consistent with a pituitary adenoma. Craniopharyngiomas are also benign masses, but they usually arise in the suprasellar region and extend down into the sella. They also frequently have cysts and calcifications and usually occur in children and in 50-to-60-year-olds. Rathke's cleft cysts are benign and usually arise in the sella, but they typically do not enhance. Malignant lesions such as lymphoma and metastases are usually more heterogeneous and less well circumscribed, and they destroy rather than remodel bone. Granulomatous processes and other infectious and inflammatory conditions are usually more infiltrative and are frequently associated with basilar meningeal enhancement. In summary, the mass is most likely an adenoma. The thickened skull and prominent frontal sinuses provide clues to the particular type of adenoma. Dr. Utz: On the basis of the imaging scans, the most likely diagnosis is a pituitary adenoma. For any pituitary lesion, it is important to evaluate for visual or other neurologic dysfunction from mass effect, for hypopituitarism from disruption of normal pituitary function, and for a syndrome associated with pituitary hormone excess. Hypopituitarism Assessing for hypopituitarism includes confirmation of normal levels of cortisol (a random or corticotropin-stimulated cortisol level >18 μg per deciliter [500 nmol per liter]), thyroid hormone (a normal free thyroxine level), gonadal steroids (regular menses in premenopausal women or a normal morning testosterone level in men), and growth hormone (normal results of growth hormone stimulation testing). Diabetes insipidus is rarely caused by a pituitary adenoma, but with other pituitary lesions and a suggestive clinical history, fluiddeprivation testing is indicated. Pituitary Hormone Excess Syndromes On the basis of their cell of origin, pituitary adenomas are subdivided into prolactinomas, somatotroph adenomas (acromegaly), corticotroph adenomas (Cushing's disease), thyrotropin-secreting adenomas, and hormonally nonfunctioning adenomas usually derived from gonadotroph cells. A substantial elevation in the prolactin level usually indicates that the lesion is a prolactinoma. A mild elevation in the prolactin level does not always indicate a prolactinoma and may be a result of disruption of the inhibitory dopamine signal from the hypothalamus (known as the stalk effect) by any disorder that affects the pituitary region; alternatively, certain medications can cause an increase in prolactin levels. Cushing's syndrome is diagnosed on the basis of elevated levels of 24-hour urinary cortisol, late-night salivary cortisol, and dexamethasone-suppressed serum cortisol. Subsequent determination of corticotropin dependence and the ruling out of an ectopic source of corticotropin confirm pituitary Cushing's syndrome. 17
The finding of an elevated serum level of insulin-like growth factor 1 (IGF-1) is suggestive of acromegaly, and the diagnosis is confirmed by lack of growth hormone suppression after oral glucose suppression testing. Thyrotropin-secreting adenomas cause elevated free thyroxine levels and nonsuppressed thyrotropin levels.
Acromegaly Acromegaly, which I believe this patient has, is due to overproduction of growth hormone. Binding of growth hormone to hepatic receptors leads to systemic release of IGF-1. Growth hormone and IGF-1 have effects on many tissues, fluid balance, and glucose homeostasis. The diagnosis should be considered in a patient with clinical findings such as prognathism, frontal bossing, deep nasolabial folds, thickened skull, widened spacing of teeth, underbite, facial edema, macroglossia, enlarged hands and feet, skin tags, excessive perspiration, acne, headache, tall stature (in those in whom the disorder develops before the completion of puberty), hypogonadism, insulin resistance or diabetes mellitus, hypertension, sleep apnea, carpal tunnel syndrome, arthralgia, cardiac hypertrophy or valvular dysfunction, and colon polyps.10,11 This patient has many clinical features of acromegaly: hypogonadism, skeletal changes, acne, glucose intolerance, sleep apnea, and arthralgias. This patient's menstrual irregularity could have been caused by hypogonadotropic hypogonadism due to disruption of normal LH and FSH release by the pituitary tumor mass12 or excessive growth hormone, which may have induced a polycystic ovary syndrome–like anovulatory state. An excess of growth hormone increases insulin resistance, possibly because of a direct cellular effect or mobilization of free fatty acids. In a study of 14 women with active acromegaly, 50% had polycystic ovaries on ultrasonography and 43% fulfilled the Rotterdam criteria for the phenotype of the polycystic ovary syndrome.13 Women with acromegaly frequently have signs and symptoms of hyperandrogenism, with normal estrogen and testosterone levels and low sex hormone–binding globulin levels. Growth hormone or IGF-1 or both may directly affect ovarian function, or growth hormone may induce these changes indirectly by means of hyperinsulinemia.12,13 This patient most likely had active acromegaly while she was pregnant, which may have contributed to her gestational diabetes; it also probably contributed to her continued glucose intolerance. This patient had several characteristics that could have led to an earlier diagnosis of acromegaly. The presence of a hypogonadotropic hypogonadism hormonal pattern during an infertility evaluation indicates a need for pituitary MRI. Her oligo-ovulation and clinical hyperandrogenism met the criteria for the polycystic ovary syndrome phenotype, and thus this case highlights the need to consider alternative causes of the polycystic ovary syndrome phenotype. Her clinical features were suggestive of acromegaly, and measurement of the serum IGF-1 level to check for growth hormone excess was indicated, as was a test for growth hormone suppression after an oral glucose load.
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Untreated acromegaly diminishes survival, particularly in those with diabetes mellitus or cardiac disease.14 The initial treatment is generally surgical resection, which was probably the procedure performed in this case. Frequently, residual tumor remains after surgery, and medical management is necessary. The primary medical therapies are somatostatin analogues, a growth hormone receptor antagonist, dopamine agonists, or a combination of these. Radiation may be necessary in some cases.15 Dr. Nancy Lee Harris (Pathology): May we have the medical students' diagnosis? A Harvard Medical Student: We thought that the most likely cause of this woman's symptoms was a growth hormone–secreting pituitary adenoma, because of the sella turcica mass and the clinical features of acromegaly. Dr. Lisa B. Nachtigall (Neuroendocrinology): We thought that this patient had acromegaly caused by a growth hormone–secreting pituitary macroadenoma. The results of visual-field testing were normal. Laboratory testing showed that the IGF-1 level was slightly elevated at 574 ng per milliliter (reference range, 114 to 492). An oral glucose-tolerance test for growth hormone suppression was markedly abnormal: after a 75-g load of glucose, the nadir growth hormone level was 72 ng per milliliter (normal, <1). Additional testing was done to evaluate other anterior pituitary functions, since in patients with a sellar mass, compression may cause dysfunction of any pituitary hormonal axis. Although the thyrotropin level was normal, the free thyroxine level was low, a feature consistent with central hypothyroidism. The stimulated cortisol level was normal. The LH, FSH, and estradiol levels were low, features consistent with central hypogonadotropic hypogonadism. The glycated hemoglobin level was slightly elevated, a feature suggestive of metabolic dysfunction associated with acromegaly. The prolactin level was slightly elevated (measurement was performed on a diluted sample), which could have been caused by cosecretion of prolactin and growth hormone or the effect of stalk compression by the tumor. Our preoperative diagnosis was acromegaly, with central hypothyroidism, and hypogonadotropic hypogonadism. Adrenal reserve was normal. We recommended transsphenoidal resection of the tumor, which was performed. Clinical Diagnosis Acromegaly due to a growth hormone–secreting pituitary macroadenoma. Dr. Andrea L. Utz's Diagnosis Acromegaly due to a growth hormone–secreting pituitary macroadenoma. Pathological Discussion Dr. Matija Snuderl: We received the tumor as multiple fragments of tissue measuring 2.0 by 1.5 by 0.4 cm in aggregate. Microscopical evaluation (Figure 2A and 19
2BFigure 2
Pathological Examination of a Specimen of the Pituitary Tumor from a
Transsphenoidal Resection.) confirmed the diagnosis of the pituitary adenoma with moderate cellular pleomorphism. Immunohistochemical studies revealed that most tumor cells were reactive for human growth hormone (Figure 2C), some tumor cells were reactive for prolactin, and occasional tumor cells were reactive for alpha subunit. Immunohistochemical staining for cytokeratin CAM 5.2 (Figure 2D) revealed a diffuse cytoplasmic pattern of positivity. The proliferation index, assessed with Ki67 immunostaining, was less than 1% (Figure 2D, inset). A low proliferation index and diffuse fibrillary CAM 5.2 staining pattern are associated with a lower risk of recurrence.16,17
Figure 2. Pathological Examination of a Specimen of the Pituitary Tumor from a Transsphenoidal Resection. Dr. Harris: Dr. Nachtigall, would you tell us how the patient is now? Dr. Nachtigall: At the patient's 6-week postoperative follow-up, a pituitary MRI scan showed no evidence of a tumor. Results of visual-field tests remained normal. There was rapid diminishing or resolution of signs and symptoms of acromegaly, including carpal tunnel syndrome, joint pains and stiffness, snoring, sweating, acne, and hirsutism, and the patient's ring size and shoe size decreased. Regular menstrual periods resumed. Fasting blood glucose levels were normal. The IGF-1 level was normal at 369 ng per milliliter. However, after an oral glucose-tolerance test, the growth hormone level remained elevated at 2.5 ng per milliliter (normal, <1). The rest of the patient's pituitary function returned to normal, as did the glycated hemoglobin level. Because of the elevated nadir growth hormone level after the oral glucose-tolerance test, we suggested that she begin medical therapy with a low dose of a somatostatin analogue. Ten weeks postoperatively, we started her on 10 mg of octreotide 20
monthly. She continued on this therapy until about 7 months postoperatively, when she wished to conceive again. Her MRI scan remained clear, and her visual fields were normal. She spontaneously conceived almost exactly 1 year postoperatively. The IGF-1 level and results of thyroid-function, glucose, and visual-field tests remained normal throughout her pregnancy, and she delivered a healthy infant. Eight months later, however, the IGF-1 level was 646 ng per milliliter, and monthly injections of octreotide were resumed. The IGF-1 level is now normal, and 2.5 years after removal of the adenoma, the patient remains well. Anatomical Diagnosis Pituitary adenoma with production of growth hormone. This case was presented at a Medical Case Conference, December 12, 2008. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Dr. Lisa B. Nachtigall for helping to prepare the case history and for providing follow-up information. Source Information From the Neuroendocrine Unit (A.L.U.) and the Departments of Radiology (P.W.S.) and Pathology (M.S.), Massachusetts General Hospital; and the Departments of Medicine (A.L.U.), Radiology (P.W.S.), and Pathology (M.S.), Harvard Medical School — both in Boston; and the Pituitary Center, Vanderbilt University Medical Center, Nashville (A.L.U.).
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