HYPERPROLACTINAEMIA

1. HYPERPROLACTINAEMIA

2. Hyperprolactinaemia results from excessive stimulation of the prolactin secreting cells in the pituitary gland and leads to a shortening of the luteal phase resulting in infertility and increased progesterone levels.

3. Prolactin is a pituitary derived hormone that: • plays a pivotal role in a variety of reproductive functions; • Is essential for normal production of breast milk following childbirth; • Modulates the secretion of pituitary hormones responsible for gonadal function including: • Luteinizing hormone (LH) • Follicle stimulating hormone (FSH)

4. There can be three types of causes: • Physiological • During pregnancy • lactation • Pharmacological • use of neuroleptics • oestrogen

5. Pathological • Primary hypothyroidism • Renal or hepatic insufficiency • Prolactin is cleared less rapidly from the systemic circulation, which results in increased blood levels of prolactin • Hypothalamic or pituitary disease interfering with the secretion of dopamine, ie, prolactinomas :

6. Prolactinomas - benign tumour (adenoma) of the pituitary gland that produces a hormone called prolactin. It is the most common type of pituitary tumour Aprolactinoma will secrete prolactin. • These tumours may interrupt dopamine delivery from the hypothalamus to the pituitary, resulting in loss of inhibition of prolactin release.

7. Cushing’s Disease : • a hormonal disorder caused by high levels of cortisol. Symptoms include upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, fatigue, weakness, high blood pressure, and mood disorders. Children tend to be obese with slowed growth rates.

8. Pituitary adenomas cause most cases of Cushing's syndrome. They are benign, or non-cancerous, tumours of the pituitary gland which secrete increased amounts of ACTH, (adrenocorticotropin), a hormone that stimulates the adrenal glands. Cushing's syndrome can also be caused by taking glucocorticoid hormones such as prednisone for asthma, rheumatoid arthritis, lupus and other inflammatory diseases, or for immunosuppression after transplantation. It may also develop because of overproduction of cortisol by the body, or adrenal tumours.

9. The effects of medications that inhibit dopamine release, thus leading to reduced inhibition and increased prolactin production: • Clomid, used for infertility, could be a factor in the development of hyperprolactinaemia which can then cause infertility. It has been implicated in the possibility of miscarriage and ectopic pregnancies as well as the development of PCOS. • Neuroleptics  phenothiazines, haloperidol • (Anti-psychotic drugs)

10. Antihypertensives  calcium-channel blockers, methyldopa • Psychotropic agents  tricyclic antidepressants • Anti-ulcer agents  H2 antagonists • Opiates • Oral contraceptives

11. Hypothyroidism(Serri, O., Chik, CL., Ur, R., Ezzat, S. 2003, ‘Diagnosis and treatment of hyperprolactinaemia’, Canadian Medical Association Journal, vol.169, no.6, pp.575-577) • In response to the hypothyroid state, a compensatory increase in the discharge of central hypothalamic thyroidotropin-releasing hormone results in increased stimulation of prolactin secretion. • Furthermore, Prolactin elimination from the systemic circulation is reduced, which contributes to increased prolactin concentrations

12. An autoimmune condition of the pituitary with lymphocytic infiltration can lead to hyperprolactinaemia and is typically noted in the postpartum phase in women of childbearing age. Spontaneous resolution is common. • Suckling in the breast-feeding woman stimulates prolactin release. As well, breast stimulation in some non-breast feeding women and rarely in some men may also cause an increase in serum prolactin levels.

13. It can also be related to Polycystic Ovarian Syndrome: • About 25% of PCOS patients exhibit elevated prolactin, known as hyperprolactinemia. • Hyperprolactinemia results from abnormal oestrogen negative feedback via the pituitary gland. • Elevated prolactin can in turn contribute to elevated oestrogen levels.

14. EPIDEMIOLOGICAL FACTORS • An excess of prolactin can be found in up to 10% of the population • The prevalence is about 5% among men who present with impotence and infertility • The rate is higher among people with specific symptoms that may be attributable to hyperprolactinaemia, that is, up to: • 9% among women with amenorrhea • 25% among women with galactorrhea • 70% among women with both amenorrhea and galactorrhea

15. CLINICAL PRESENTATIONS(Serri, O., Chik, CL., Ur, R., Ezzat, S. 2003, ‘Diagnosis and treatment of hyperprolactinaemia’, Canadian Medical Association Journal, vol.169, no.6, pp.575-577) • PREMENOPAUSAL WOMEN • Marked prolactin excess (<100ug/L [normally >25ug/L] is associated with hypogonadism, galactorrhea and amenorrhea • Moderate prolactin excess (51 – 75ug/L) is associated with oligomenorrhea • Mild prolactin excess (35 – 50ug/L) is associated with short luteal phase, decreased libido and infertility

16. Increased body weight may be associated with prolactin-secreting pituitary tumour • Osteopenia is present mainly in people with associated hypogonadism • Degree of bone loss is related to duration and severity of hypogonadism

17. MEN • Hyperprolactinaemia presents with decreased libido, impotence, decreased sperm production, infertility, and, rarely, galactorrhea • Impotence is unresponsive to testosterone treatment and is associated with decreased muscle mass, body hair and osteoporosis.

18. TREATMENT PROTOCOL

19. Provide a dopaminergic reaction that will inhibit prolactin, therefore normalising the luteal phase and increasing the possibility of pregnancy and the prevention of miscarriage • False Unicorn Root • Dysfunction in the female reproductive system, threatened miscarriage and infertility (Bone 2003) • Kings American Dispensary (1898) listed it to remove the tendency to repeated and successive miscarriages and for atrophy of the reproductive organs.

20. Glycyrrhiza glabra • Glycyrrhizin has been shown to lower testosterone (Armanini,D., Bonanni,G., Palermo,M., 1999, ‘Reduction of serum testosterone in men by licorice’, New England Journal of Medicine, Oct 7;341(15);1158) • Licorice and peony have been shown to act directly on the pituitary gland to counteract hyperprolactinaemia (Bone 2004). It has been shown to stimulate the dopamine receptors and stimulate the ovarian production of oestrogen by stimulating aromatase activity.

21. Paeonia lactiflora • Is part of the shakuyaku-kanzo-to formula, with licorice, used to improve fertility in women affected by PCOS (Takahashi,K., Kitao,M., 1994, ‘Effect of TJ-68 (shakuyaka-kanzo-to) on polycystic ovarian disease’ International Journal of Fertility and Menopausal Studies, 39:69-76) • In another study, 90% of women taking a Licorice and peony combination showed decreased progesterone levels and 25% became pregnant (Takahashi,K., Yoshino,K., Shirai,T., Nishigaki,A., Araki,Y., Kitao,M., 1988, ‘Effect of a traditional herbal medicine (shakuyaka-kanzo-to) on testosterone secretion in patients with polycystic ovary syndrome detected by ultrasound’, Nippon Sanka Jujinka Gakkai Zasshi, Jun;40(6):789-92)

22. Peony has been shown to reduce sexual dysfunction in men, reportedly caused by neuroleptic-induced hyperprolactinemia. (Peony monograph, Alternative Medicine Review, Oct 2001 v6 i5 p495) • Women with dysmenorrhea and/or amenorrhea due to use of the neuroleptic drug risperidone benefited from shakuyaku-kanzo-to according to another report (Peony monograph, Alternative Medicine Review, Oct 2001 v6 i5 p495)

23. Asparagus racemosus(http://www.shatavari.com/) • Shativari is well known for its effects on the female reproductive system. For balancing hormonal system of women, Shativari may be used for regulating menstruation and ovulation, improving lactation, decreasing morning sickness, infertility, Menopause, Leukorrhea, inflammation of sexual organs, and general sexual debility. • The male reproductive system will also benefit from Shativari as it may be used in cases of sexual debility, impotence, Spermatorrhea, and inflammation of Sexual organs.

24. Vitex agnus-castus • Shown to have dopaminergic activity associated with the inhibition of prolactin synthesis and release in hyperprolactinaemia(Heinrich et al 2004) • 52 women with luteal phase defects due to latent hyperprolactinaemia were given a daily dose was one capsule (20 mg) Vitex agnus castus preparation and placebo, respectively. 37 complete case reports (placebo: n = 20) after 3 month of therapy were statistically evaluated. The prolactin release was reduced after 3 months, shortened luteal phases were normalised and deficits in the luteal progesterone synthesis were eliminated. (Milewicz, A., Geidel, E., Sworen, H., Sienkiewicz, K., Jedrzeiak, J., Teucher, T., Schmitz, H. 1993, ‘Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study’, Arzneimittelforschung, vol.43, no.7, pp.752-6)

25. Vitex is a popular treatment for mastalgia. Two randomised, double blind studies confirm its usefulness as a treatment in premenstrual mastalgia. According to one study, symptom relief was experienced after the first month of treatment, with continued improvements after the second and third months. In each study, chaste tree reduced serum prolactin levels.(Wuttke,W., Jerry,H., Christoffel,V., Spengler,B., Seldiova-Wuttke,D. 2003, ‘Chaste tree (Vitex agnus castus)- pharmacology and clinical indicaqtions’, Phytomedicine, vol.10, pp.348-357) Prolactin works like a stress barometer. Evidence exists to prove that vitex can clinically lower prolactin levels. Research from both in vitro and in vivo studies have indicated that vitex acts on the D2 receptors to decrease prolactin levels. (Braun, L. 2006, “Vitex agnus-castus: Chasteberry”, The Journal of Complementary Medicine, vol.5, no.4, pp.71-71)

26. Deal with the stress, anxiety and other nervous system issues that may be affecting the prolactin levels • Hypericum perforatum • Panax ginseng • Glycyrrhiza glabra • Schisandra sinensis • Withania somnifera • Prevention of osteoporosis • Red Clover’s effect on preventing bone loss after menopause. • Support the treatment of the pituitary tumour if present

27. Liver support to deal with any dysfunction and to enhance the metabolism of hormones • Schisandra sinensis • liver detoxification, hepatoprotective, antioxidant, and anti-inflammatory (Heinrich et al 2004) • Silybum marianum • Other considerations • Research has shown that elevated levels of homocysteine can be responsible for recurrent miscarriages (Ronnenberg AG., Goldman MB., Chen D., Aitken IW., Willett WC., Selhub J & Xu X, 2002 ‘Preconception homocysteine and vitamin B status and birth outcomes in Chinese women’ American Journal of Clinical Nutrition, 76(6):1385-91) • Beer increases prolactin levels and must be avoided (Bone 2004)