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Home , Hyperprolactinaemia, Quinagolide

Archives of Reproductive Medicine and Sexual Health ISSN: 2639-1791 Volume 1, Issue 2, 2018, PP: 61-67 : A Monster Between the Woman and Her Conception *Seriki A. Samuel1, Odetola O. Anthony2 1Department of Human Physiology, College of Medicine, Bingham University, Karu, Nigeria. 2Department of Human Physiology, College Medical Sciences, NnamdiAzikwe University, Awka, Nigeria. [email protected] *Corresponding Author: Seriki A. Samuel, Department of Human Physiology, College of Medicine, Bingham University, Karu, Nigeria.

Abstract Hyperprolactinaemia is the presence of abnormally high levels of in the blood. Normal levels are less than 5000 ml U/L [20ng/mL or µg/L] for women, and less than 450 ml U/L for men.Prolactin is a produced by the adenohypophysis (also called anterior pituitary) that is primarily associated with milk production and plays a vital role in breast development during . Hyperprolactinaemia may cause (production and sp; ontaneous ejection of without pregnancy or childbirth). It also alters/disrupts the normal in women. In other women, may cease completely, resulting in . In the man, it could causeerectile dysfunction.The present study is to review the pathophysiology of the abnormality in the woman, and how it relates to the functioning of the hypothalamo- hypophyseal-gonadal system. The article also looks at the effect of hyperprolactinaemia on the fertility of the woman, and attempts to proffer non-surgical remedy to the condition. Keywords: Galactorrhea, adenohypophysis,,, amenorrhoea, macroprolactin, microprolactin

Introduction It is synthesized by the anterior pituitary lactotrophs and regulated by the hypothalamic–pituitary axis Hyperprolactinaemia, which is a high level of through the release of , which acts as a prolactin in the blood can be a part of normal prolactin inhibitory factor[2]. physiological changes in the body during pregnancy and . Pathologically, it can be caused During pregnancy and there is considerable by diseases a and pituitary hyperplasia of lactotrophs, resulting in up to a ten- gland. It may also be caused by disruption of the fold increase in the circulating levels of prolactin. normal regulationffecting of the prolactin levels by drugs, medicinal herbs and heavy metals inside the body. pregnancy, predominantly the change in Hyperprolactinaemia may also be the result of disease levels.This effect Subsequently, is secondary prolactin to the levels hormonal return tochanges baseline of of other organs such as the liver, kidneys, ovaries and concentrations within 6 months of delivery [3]. [1]. Dopamine is the predominant physiological prolactin The is a small bean-shaped gland inhibitory factor[2]. situated at the base of the brain. Despite its small size, Approximately 80–90% of prolactin is monomeric (23 human body. Its hormones help regulate important kDa), and this is its most potent biological form; 8–20% functionsthe pituitary such gland as growth, influences metabolism, nearly every blood part pressure of the is dimeric (45–50 kDa); and 1–5% is polymeric (150 and reproduction. Prolactin is one of thehormones. kDa). The latter fraction is called macroprolactin[4]. Prolactin is a single-chain polypeptide hormone which In women, a high blood level of prolactin often causes hypoestrogenism (low level of oestrogen in the hasArchives effects of onReproductive reproduction, Medicine lactation andand Sexualmetabolism. Health V1 . I2 . 2018 61 Hyperprolactinaemia: A Monster Between the Woman and Her Conception blood) with anovulatoryinfertility and a decrease in Likewise, an abnormality of a division of the pituitary menstruation. In some women, menstruation may stalk could also cause hyperprolactinaemia. Other disappear altogether (amenorrhoea). In others, causes include chronic renal failure, , bronchogenic carcinoma and . Some may change. Women who are not pregnant or nursing women with polycystic ovary syndrome may have maymenstruation begin producing may become breast irregular mil kor. menstrual Some women flow mildly-elevated prolactin levels. may experience a loss of (interest in sex) and Non-puerperal mastitis may induce transient breast pain, especially when prolactin levels begin hyperprolactinemia (neurogenic hyperprolactinemia) of about three weeks’ duration; conversely, tissue changes in the breast. Intercourse may become hyperprolactinemia may contribute to non-puerperal to rise for the first time, as thevaginal hormone drynes promotess due mastitis[5]. to hypoestrogenism. Hyperprolactinaemia that is secondarydifficult or to painful pituitary because adenom ofa may cause Prolactinoma could also be a tumor that develops in and visual blurredness caused by the enlarged the pituitary gland with an unknown cause. pituitary pressing against the adjacent optic chiasm. Apart from diagnosing hyperprolactinaemia and In men, the most common symptoms of , prolactin levels are often checked hyperprolactinaemia are decreased libido, sexual , dysfunction, , infertility, and when there is doubt as to whether they have had an . Seeing that men have no reliable epilepticby physicians seizur ine patients or a non-epileptic that have suffered seizure .a Shortly indicator such as menstruation to signal the problem, after epileptic , prolactin levels often rise, many men with hyperprolactinaemia being caused whereas they are normal in non-epileptic seizures. by a may delay going to the doctor until they start having headaches or eye problems. Medical Causes They may not recognize a gradual loss of sexual Prolactin secretion in the pituitary is normally function or libido. suppressed by the brain chemical dopamine. Drugs Because of hypoestrogenism and hypoandrogenism, hyperprolactinaemia can lead to . or deplete dopamine storage in the brain may cause thethat pituitary block the to effectssecrete more of dopamineprolactin. at These the drugs pituitary Causes include the typical : such Physiological Causes as (Thorazine), and butyrophenones such as (Haldol); atypical antipsychotics Physiological (non-pathological) causes include: pregnancy, breastfeeding, and mental . such as (Risperdal) and (Invega); gastroprokinetic drugs used to treat gastro- Pathological Causes x and medication-induced nausea Prolactinoma or other tumours arising in or near (such as that from ). oesophageal reflu the pituitary — such as those that cause In particular, the dopamine antagonists and are both powerful (hypothalamus) to the prolactin-secreting cells of prolactin stimulators and have been used to stimulate may block the flow of dopamine from the brain pituitary thereby hyperprolactimaemia. breast milk secretion for decades. However, since hyperprolactinaemia is a condition in which a non- prolactin is antagonized by dopamine and the body cancerous tumor (adenoma) of the pituitary gland in depends on the two being in balance, the risk of the brain overproduces the hormone prolactin. The prolactin stimulation is generally present with all drugs that deplete dopamine, either directly or — estrogen in women and in men. indirectly. major effect is decreased levels of some sex hormones Although prolactinoma isn’t life-threatening, it can Symptoms of Hyperprolactinaemia impair vision, cause infertility and produce other There may be no noticeable signs or symptoms hormone-producing tumor that can develop in the from prolactinoma. However, signs and symptoms pituitaryeffects. gland. Prolactinoma is the most common type of can result from excessive prolactin in your blood

62 Archives of Reproductive Medicine and Sexual Health V1 . I2 . 2018 Hyperprolactinaemia: A Monster Between the Woman and Her Conception (hyperprolactinemia) or from pressure on surrounding Risk Factors tissues from a large tumor. Because elevated prolactin Most occur in women between 20 and can disrupt the reproductive system (), 34 years old, but can occur in both sexes at any age. some of the signs and symptoms of prolactinoma are The disorder is rare in children. specificIn females, to females prolactinoma or males. can cause:Irregular menstrual periods (oligomenorrhea) or no menstrual periods (), Milky discharge from the breasts (galactorrhea) when not pregnant or breast- feeding, Painful intercourse due to vaginal dryness Acne and excessive body and facials, and hair growth (hirsutism). In males, prolactinoma can cause:Erectile dysfunction, Decreased body and facial hair, and enlarged breasts (gynecomastia) In both sexes, prolactinoma can cause:Low bone density, Reduction of other hormone production by the pituitary gland (hypopituitarism) as a result of tumor pressure, Loss of interest in sexual activities, Figure1. Showing the positions of the hypothalamus Headaches, and Visual disturbances, and Infertility and the pituitary gland Women tend to notice signs and symptoms earlier Complications than men do, when tumors are smaller in size, probably because they’re alerted by missed or Complications of prolactinoma may include: irregular menstrual periods. Men tend to notice signs • Vision loss. Left untreated, a prolactinoma may and symptoms later, when tumors are larger and more grow large enough to compress the optic nerve. likely to cause or vision problems. • Hypopituitarism. With larger prolactinomas, pressure on the normal pituitary gland can cause 10 mm in diameter) and macroadenomas (>10 mm dysfunction of other hormones controlled by the inProlactinomas diameter) and are it is classified estimated as that microadenomas 10% of healthy (< pituitary, resulting in hypothyroidism, adrenal unselected people will have radiological evidence of pituitary adenomas.6[Serri O] Pituitary imaging should be considered before starting • insufficiencyBone loss (osteoporosis). and growth hormone Too much deficiency. prolactin treatment, as this can result in reduction in the size can reduce production of the hormones estrogen of microprolactinomas and underdiagnosis. Many and testosterone, resulting in decreased bone authorities suggest, however, that pituitary MRI is not density and an increased risk of osteoporosis. • Pregnancy complications. During a normal no other clinical or biochemical features of pituitary pregnancy, the production of estrogen increases. necessary if the prolactin level is < 1000 mIU/l and disease are present. In the event of pregnancy and presence of a large Management of prolactin excess Indications for prolactinoma, the high levels of estrogen may cause tumor growth and associated signs and symptoms, such as headaches and changes in treatment can be divided into thoserelated to the effects vision. of hyperprolactinaemia (anovulationand infertility/ reduced bone density/galactorrhoea) andthose Management related to the mass effect of the prolactinoma(visual Treatment is usually medical or surgical and, very [7;8].field defects due to pressure on the opticchiasma/ rarely, radiotherapy. hypopituitarism/cranial nerve defects/headaches) Archives of Reproductive Medicine and Sexual Health V1 . I2 . 2018 63 Hyperprolactinaemia: A Monster Between the Woman and Her Conception Medical Treatment The echocardiographic and microscopic features in these cases were similar to those seen in cardiac Correction of hyperprolactinaemia using dopamine valvular disorders associated with ergot alkaloids, agonists has been reported to restore in suggesting causation by the ergot features of approximately 90% of women with . A possible explanation is that cabergoline secondary to hyperprolactinaemia and result in pregnancy in 80–85% [8;12]. receptors 2B (HTR2B) located on the heart valves andhas that a high activation affinity of for these the receptors 5-hydroxytryptamine may lead to both microprolactinomas and macroprolactinomas; theDopamine preparations agonists commonly are the used first-line are treatment for is, therefore, required with higher doses of ergot- and cabergoline. derivedmitogenesis dopamine and fibroblast agonist, and proliferation. the Committee Caution on Safety of Medicines (UK) guidance recommends Treatment is usually medication with dopamine 6–12 monthly echocardiography for people receiving agonists such as cabergoline[12], bromocriptine cabergoline[17]. (often preferred when pregnancy is possible) [13; 8] and less frequently . A new drug in use is The drug has a very long elimination half-life and can, norprolac[14]with the active ingredient . therefore, be administered once or twice a week. It has is also used. been shown [8]to result in resumption of ovulation in 95% of cases and reduction of tumour size in 80% of Vitexagnus-castus extract can be tried in cases of mild cases. hyperprolactinaemia[15]. No data have shown cabergoline to be unsafe for Bromocriptine women wishing to become pregnant, but there are This has been used in clinical practice for more than 25 years. Bromocriptine has approved for use in this context. a relatively short half-life and is, therefore, taken 1–3 insufficient safety data available and it is yet to be Data on fetal exposure to cabergoline in early [8].It has been shown to restore ovulation pregnancy have been reported in over 350 cases, with in 80–90% of women and to reduce the size of no increase in adverse outcomes[18]. prolactinomastimes/day in 70% of cases [8]. Quinagolide (Terguride) and headache symptoms within days of treatment. This is a non-ergot dopamine agonist that has been BromocriptineIt has also been reported has a high to improve prevalence visual field of adverse defects in reducing prolactin levels and the treatment of and postural hypotension (25%). [8]. galactorrhoea,reported to have as well similar as restoring efficacy menses to bromocriptine and fertility. gastrointestinal effects (nausea 30%, vomiting 20%) It has a long half-life and is, therefore, administered pregnancy and long-term follow-up data up to 9 years, bromocriptine, and as a non-ergot derived dopamine ofThe children drug born has to a mothers well-established treated with safety bromocriptine profile in agonist,once daily. the It risk has of a valvularbetter adverse-effect abnormalities profileis likely than to in early pregnancy, are very reassuring [16]. be lower. Cabergoline of quinagolide and the concerns regarding valvular bromocriptine in lowering prolactin levels, with heartGiven diseasethe efficacy with and cabergoline, better adverse-effect many centres profile now This has been shown to be more effective than use quinagolide as the dopamine agonist of choice in the treatment of hyperprolactinaemia. However, there substantially fewer adverse effects and higher patient are much fewer safety data on its use in pregnancy, disease.compliance. A number A potentially of reports significant [17;13] have shortcoming described is the possible negative effect on cardiac valvular [8]. high doses of cabergoline, i.e. a total daily dosage of 4 although no teratogenic effects have been documented Surgical Management mgcardiac in Parkinson’s valvular insufficiency disease, which in people is much who higher received than that used for the treatment of hyperprolactinaemia. Surgical Management involves the removal of

64 Archives of Reproductive Medicine and Sexual Health V1 . I2 . 2018 Hyperprolactinaemia: A Monster Between the Woman and Her Conception prolactinoma (tumour) by surgery. Details of this is women presenting with infertility and compared the not within the scope of this article. levels with those in 58 women who had intrauterine contraceptive devices showed that the prolactin Management of Hyperprolactinaemia and pregnancy infertile group compared with the control group and Treatment of hyperprolactinaemia in women who theconcentrations progesterone were concentrations significantly were higherlower [10]. in the wishto have a pregnancy is dependent on the size of Another study on the prevalence of hyperprolactinaemia theprolactinoma and the clinical presentation. Medical in infertile women who had regular menstrual treatment is preferred to surgery where possible and will generally provide optimal control in most cases endometrial histology with those of infertile women with microprolactinomas or macroprolactinomas withcycles normal correlated prolactin their hormone levels. Hyperprolactinaemia profiles and luteal with no supracellar extension. Because of its better was noted in 15 of 130 infertile women (11.5%) with regular menstrualcycles and no galactorrhoea. There was no increase in theincidence of inadequate medicalestablished treatment safety profile, in macroprolactinomas bromocriptine is generally is that the first line of treatment. One reason for failure of luteal phase, diagnosed histologically, in women these tumours may have a substantial cystic element who had raised serum prolactin. Result showed that the evidence for usefulness of serum prolactin dopamine agonist treatment and which will require measurement in the evaluation of luteal function in which causes a mass effect, which will not shrink with surgical decompression. infertility was scanty [11]. Discussion and Conclusion of microprolactinomas in pregnancy is low (approximatelyThe risk of 2.6%).clinically However, significant this risk enlargement is much Discussion higher with macroprolactinomas (30–35%) and 8.5% High levels of prolactin result in anovulation, secondary of these may require surgery [7;8]. to inhibition of pulsatility. It An MRI should be performed if the woman develops has been suggested that raised prolactin levels can visual symptoms of mass expansion. The risk of also compromise follicular development and reduce tumour expansion during pregnancy in women with corpus luteal sensitivity to luteinising hormone with a macroprolactinomas is quite high that many centres resulting reduction in progesterone secretion[9;19]. recommend continuation of medical treatment However, ovarian sensitivity to prolactin is very throughout the pregnancy with monitoring of in some cases but cause anovulation and amenorrhoea with prolactinoma experience persistent breast invariable; others [20].moderately elevated levels may have no effect milkvisual production fields at least after each they trimester. cease breastfeeding,Some women Hyperprolactinaemia may have a more subtle and dopamine agonist therapy may have to be recommenced in such cases. hormonal milieu, without necessarily suppressing Hyperprolactinaemia and Female ovulationinfluence on[9]. follicularWomen function with raised and the serum intra-ovarian prolactin Reproductive Function Female patients with hyperprolactinaemia have prolactinhad significantly were associated higher levels with of a marked prolactin reduction in their severally presented infertility. What is even inantral follicle-stimulating follicular fluid. The hormone high levels (FSH) of intra-follicular and estradiol more controversial is the association between hyperprolactinaemia and infertility in the presence of ovulation and regular menstrual cycles[9]. levelsHyperprolactinaemia in the antral follicular and female fluid. reproductive function The incidence of raised prolactin concentrations thatthis marked reduction in intra-follicular activity in infertile but ovulatory women ranges from 3.8– were severely deficient in granulosa cells. It is of note 11.5% [7]. levels of FSH orestradiol in the peripheral plasma. A study revealed that luteal phase serum prolactin Hyperprolactinaemiawas notassociated with is any therefore significant associated changes with in the a and progesterone concentrations in 31 ovulatory marked reduction inintra-ovarian activity, the extent Archives of Reproductive Medicine and Sexual Health V1 . I2 . 2018 65 Hyperprolactinaemia: A Monster Between the Woman and Her Conception of which may not be alwaysapparent from the levels to solve the conception challenges associated with of circulating hormone levels. elevated level of serum prolactin and other attendant health challenges. In a study by Demura et al, prolactin was noted to directly suppress both progesterone and 17 References beta-estradiol secretion by the ovaries This [21]. [1] Mancini T, Casanueva FF, Giustina A. may explain the hypogonadismis associated with “Hyperprolactinemia and prolactinomas”. hyperprolactinaemia. and Metabolism Clinics of North Hyperprolactinaemia and America. 2008;37 (1): 67–99, viii. Raised levels of prolactin can result in suppression [2] Molitch ME. Prolactin in human reproduction. In: of luteinising hormone secretion and inhibition of ovulation and thus be associated with infertility. 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Citation: Seriki A. Samuel, Odetola O. Anthony. Hyperprolactinaemia: A Monster Between the Woman and Her Conception. Archives of Reproductive Medicine and Sexual Health . 2018; 1(2): 61-67. Copyright: © 2018 Seriki A. Samuel, Odetola O. Anthony. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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