Abstract
Hyperprolactinemia is associated with suppression of the hypothalamic- pituitary–gonadal axis and consequent hypogonadism, manifesting loss of libido, infertility and osteoporosis long-term in both male and female patients, with associated menstrual irregularities, amenorrhea and galactorrhea in women and erectile dysfunction in men. The primary goals of therapy in patients harboring prolactinoma are control of tumor size and normalization of serum PRL, with restoration of gonadal and sexual function and fertility. Clinical manifestations of hypogonadism have variable consequences depending on the age and sex of the patient and desire for fertility. Careful consideration of clinical consequences of hyperprolactinemia in relation to age and sex should help guide therapeutic decision making. Another important consideration in attaining our treatment goals in patients harboring microprolactinomas, is the observation that greater than 90% of microprolactinomas do not enlarge, when followed for 10 years. Treatment options for the management of microprolactinomas include observation alone, with monitoring of serum prolactin levels every 6–12 months, vs initiation of dopamine agonist therapy vs gonadal steroid hormone replacement (using the oral contraceptive or other combination estrogen and progesterone replacement regimens in females or testosterone replacement therapy in males). In the present review, current data related to clinical consequences of microprolactinomas and treatment outcomes at different stages in the lifespan are reviewed, with a suggested algorithm as to whether to treat or not, and an appropriate therapeutic regimen to institute.
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References
Gillam MP, Molitch ME, Lombardi G, Coloa A (2006) Advances in the treatment of prolactinomas. Endocr Rev 27:485
Freeman ME, Kanyicska B, Lerant A, Nagy G (2000) Prolactin: structure, function, and regulation of secretion. Physiol Rev 80:1523–1631
Schlechte J, Dolan K, Sherman B, Chap-ler F, Luciano A (1989) The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 68:412–418
Jeffcoate WJ, Pound N, Sturrock ND, Lambourne J (1996) Long-term follow-up of patients with hyperprolactinaemia. Clin Endo 45:299–303
Rigg LA, Lein A, Yen SS (1977) Patterns of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 129:454–456
Dinč H, Esen F, Demirci A, Sari A, Resit GH (1998) Pituitary dimensions and volume measurements during pregnancy and postpartum. MRI Assess Acta Radiol 39:64–69
Elster AD, Sanders TG, Vines FS, Chen MY (1991) Size and shape of the pituitary gland during pregnancy and post partum Measurement with MR imaging. Radiology 181:531
Gonzales JG, Elizondo G, Saldivar D, Nanez H, Todd LE, Villarreal JZ (1988) Pituitary gland growth during normal pregnancy. An in vivo study using magnetic resonance imaging. Am J Med 85:217–220
Huang W, Molitch ME (2019) Pituitary tumors in pregnancy. Endocrinol Metab Clin North Am 48:569–581
Molitch ME (2015) Endocrinology in pregnancy: management of the pregnant patient with a prolactinoma. Eur J Endocrinol 172:R205–R213
Balint-Perić LA, Prelević GM (1997) Changes in prolactin levels with the menopause: the effects of estrogen/androgen and calcitonin treatment. Gynecol Endocrinol 11:275–280
Reyes FI, Winter JS, Faiman CI (1977) Pituitary-ovarian relationships preceding the menopause. A cross-sectional study of serum follice-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone levels. Am J Obstet Gynecol 129:557–564
Karunakaran S, Page RC, Wass JA (2001) The effect of the menopause on prolactin levels in patients with hyperprolactinaemia. Clin Endocrinol 54:295–300
Dekkers OM, Lagro J, Burman P, Jorgensen JO, Romijn JA, Pereira AM (2010) Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta- analysis. J Clin Endocrinol Metab 95:43–51
Hu J, Zheng X, Zhang W, Yang H (2015) Current drug withdrawal strategy in prolactinoma patients treated with cabergoline: a systematic review and meta- analysis. Pituitary 18:745–751
Mallea-Gil MS, Manavela M, Alfieri A, Ballarino MC, Chervin A, Danilowicz K, Diez S et al (2016) Prolactinomas: evolution after menopause. Arch Endocrinol Metab 60:42–46
Santharam S, Athanasios F, Arlt MW, Ayuk J, Gittoes N, Toogood A, Karavitaki N (2018) Impact of menopause on outcomes in prolactinomas after dopamine agonist treatment withdrawal. Clin Endocrinol 89:346–353
Indirli R, Ferrante E, Sala E, Giavoli C, Mantovani G, Arosio M (2019) Cabergoline withdrawal before and after menopause: outcomes in microprolactinomas. Horm Cancer 10:120–127
Devi Y, Halperin J (2014) Reproductive actions of prolactin mediated through short and long receptor isoforms. Mol Cell Endocrinol 382:400–410
Mcneilly AS, Robinson JC, Houston MJ et al (1983) Release of oxytocin and prolactin in response to suckling. Br Med J 286:257–259
Brown RS, Herbison AE, Grattan DR (2014) Prolactin regulation of kisspeptin neurons in the mouse brain and its role in the lactation-induced suppression of kisspeptin expression. J Neuroendocrinol 26:898–908
Demura R, Ono M, Demura H, Shizume K, Oouchi H (1982) Prolactin directly inhibits basal as well as gonadotropin-stimulated secretion of progesterone and 17b-estradiol in the human ovary. J Clin Endocrinol Metab 54:1246–1250
Krasnow JS, Hickey GJ, Richard JS (1990) Regulation of aromatase mRNA and estradiol biosynthesis in rat ovarian granulosa and luteal cells by prolactin. Mol Endocrinol 4:13–22
Dorrington JH, Gore-Langton RE (1982) Antigonadal action of prolactin: further studies on the mechanism of inhibition of follicle-stimulating hormone-induced aromatase activity in rat granulosa cell cultures. Endocrinology 110:1701–1707
Bouilly J, Sonigo C, Auffret J et al (2012) Prolactin signaling mechanisms in ovary. Mol Cell Endocrinol 356:80–87
Seppala M, Ranta T, Hirvonen E (1976) Hyperprolactinaemia and luteal insufficiency. Lancet 31:229–230
Mazziotti G, Mancini T, Mormando M, De Menis E, Bianchi A, Doga M, Porcelli T, Vescovi PP, De Marinis L, Giustina A (2011) High prevalence of radiological vertebral fractures in women with prolactin-secreting pituitary adenomas. Pituitary 14:299–306
Schlechte J, el-Khoury G, Kathol M et al (1987) Forearm and vertebral bone mineral in treated and untreated hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 64:1021–1026
Klibanski A, Biller BMK, Rosenthal DI, Schoenfeld DA, Saxe V (1988) Eects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 67:124–130
Seriwatanachai D, Krishnamra N, van Leeuwen JPTM (2009) Evidence for direct effects of prolactin on human osteoblasts: inhibition of cell growth and mineralization. J Cell Biochem 107:677–685
Tomlinson JW, Holden N, Hills RK et al (2001) Association between premature mortality and hypopituitarism. West Midlands prospective hypopituitary study group. Lancet 357:425–431
Kloner RA, Carson C 3rd, Dobs A, Kopecky S, Mohler ER 3rd (2016) Testosterone and cardiovascular disease. J Am Coll Cardiol 67:545–557
Santoro N (2011) Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab 96(11):3281–3288
Berinder K, Stackenas I, Akre O, Hirschberg AL, Hulting AL (2005) Hyperprolactinaemia in 271 women: up to three decades of clinical follow-up. Clin Endocrinol 63:450–455
Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF (1994) A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline comparative study group. N Engl J Med 331:904–909
Dekkers OM, Lagro J, Burman P, Jørgensen JO, Romijn JA, Pereira AM (2010) Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta- analysis. J Clin Endocrinol Metab 95(43–51):89
Kharlip J, Salvatori R, Yenokyan G, Wand GS (2009) Recurrence of hyperprolactinemia after withdrawal of long-term cabergoline therapy. J Clin Endocrinol Metab 94:2428–2436
Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JAH (2011) Diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96:273–288
Colao A, Vitale G, Cappabianca P, Briganti F, Ciccarelli A, De Rosa M, Zarrilli S, Lombardi G (2004) Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treatment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis. J Clin Endocrinol Metab 89:1704–1711
Mancini T, Casanueva FF, Giustina A (2008) Hyperprolactinemia and Prolactinomas. Endocrinol Metab Clin N Am 37:67–99
Casanueva FF, Molitch ME, Schlechte JA et al (2006) Guidelines of the Pituitary Society for the diagnosis and management of prolactinoma. Clin Endocrinol 65:265–273
Corenblum B, Donovan L (1993) The safety of physiological estrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinemia. Fertil Steril 59:671–673
Lebbe M, Hubinont C, Bernard P, Maiter D (2010) Outcome of 100 pregnancies initiated under treatment with cabergoline in hyperprolactinemic women. Clin Endocrinol 73:236–242
Ono M, Miki N, Amano K, Kawamata T, Seki T, Makino R, Takano K et al (2010) High-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroproalctinomas. J Clin Endocrinol Metab 95:2672–2679
Maiter D (2016) Prolactinoma and Pregnancy: From wish to conception. Ann d’ Endocrinol 77:128–134
Boardman HM, Hartley L, Eisinga A, Main C, iFiguls MR, Cosp X, Gabriel Sanchez R, Knight B (2015) Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD002229.pub4
Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N, Troendle JF, Nelson LM (2009) Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab 94:2277–2283
Mah PM, Webster J, Jönsson P, Feldt-Rasmussen U, Koltowska-Häggström M, Ross RJ (2005) Estrogen replacement in women of fertile years with hypopituitarism. J Clin Endocrinol Metab 90:5964–5969
Serafini P, Motta EL, White JS (2001) Restoration of ovarian cyclicity and ovulation induction in hypopituitary women. In: Bronstein MD (ed) Pituitary tumors in pregnancy. Kluwer Academic Publishers, Boston, pp 173–194
Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ et al (2018) Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 103:1715–1744
Ribeiro RS, Abucham J (2009) Recovery of persistent hypogonadism by clomiphene in male with prolactinomas under dopamine agonist treatment. Eur J Endocrinol 161:163–169
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Bonert, V. Do nothing but observe microprolactinomas: when and how to replace sex hormones?. Pituitary 23, 307–313 (2020). https://doi.org/10.1007/s11102-020-01039-x
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DOI: https://doi.org/10.1007/s11102-020-01039-x