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Isolated prolactin deficiency: a case report
Vol. 58, No.5, November 1992
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright © 1992 The American Fertility Society
Isolated prolactin deficiency: a case report
Richard J, Falk, M.D.* Division of Reproductive Endocrinology and Infertility, Columbia Hospital for Women, Washington, D.C.
Hypoprolactinemia consequent to hypophysectomy or pharmacological suppression has been reported to adversely affect the luteal phase of the menstrual cycle (1). Although these are nonphysiological states that could as well affect the ovulatory process by other mechanisms, some authorities have concluded that a minimal amount of the hormone (1 to 3 ng/mL) is necessary for normal ovulatory function (2). An isolated prolactin (PRL) deficiency, unaccompanied by pharmacological or surgical perturbations, could shed light on the role of the hormone on ovulation, but the condition is uncommon, with only three such patients having been reported (3, 4). The present case report extends this small data base by describing a patient with isolated PRL deficiency, alactogenesis, and irregular ovulation. CASE REPORT
The patient is a 36-year-old gravida 2, para 2, who had experienced normal childhood and adolescent development. After spontaneous menarche at age 13, her menses were grossly irregular, for which oral contraceptives were started at age 16. Desirous of pregnancy at age 30, the medication was discontinued, and she resumed her pretreatment oligomenorrheic pattern. Physical examination at that time revealed a woman with normal secondary sex characteristics. A serum PRL of <0.1 ,ug/L ruled out hyperprolactinemia as a cause of the ovulatory disturbance, and after successful induction of withdrawal bleeding by administration of medroxyprogesterone acetate (MPA, Provera; The Upjohn Co, Kalamazoo, MI), 10 mg/d for 7 days, she was treated
Received March 27, 1992; revised and accepted July 7, 1992.
* Reprint requests: Richard J. Falk, M.D., Division of Reproductive Endocrinology and Infertility, Columbia Hospital for Women, 2440 M Street, NW, Suite 401, Washington, D,C. 20037.
1060
Falk
Communications-in-brief
with clomiphene citrate (CC, Clomid; Marion Merrell Dow, Inc., Cincinnati, OH). At a dose of 50 mg/d for 5 days, basal temperatures remained monophasic, and the CC was increased to 100 mg/d. Although a thermal shift occurred at this dose, the luteal phase was short «8 days), and the medication was increased to 150 mg/d for 5 days. She conceived after two cycles of this regimen and had an uneventful pregnancy, culminating in a vaginal delivery with neither intrapartum nor postpartum complications. The puerperium was characterized by alactogenesis. She remained anovulatory, and oral contraception was reinstituted after several months. Three years later (February 1989), she was again successfully treated with CC, 150 mg/d, and subsequent to the uncomplicated birth of her second child, she again failed to establish lactation. After remaining amenorrheic for 1 year, with occasional MPA-induced withdrawal bleeding, she was referred to the endocrine service for evaluation. There was no family history of problems with lactation, irregular or absent menses, infertility, or musculoskeletal abnormalities. Physical examination revealed a well-developed woman, 165 cm tall, 61.25 kg, with a normal female body habitus and hair distribution. Her breasts were Tanner stage V, without masses or nipple discharge. The uterus was of normal size, shape, and consistency, and no adnexal masses were present. Hormone assays, performed by commercially available radioimmunoassay, were as follows: serum PRL, <0.1 ,ug/L (repeated) (normal limits [NL] = 1 to 18); estradiol, 16 and 29 pg/mL (NL = >40); follicle-stimulating hormone, 3.3 mIU /mL (NL = 2 to 9); luteinizing hormone (LH), 6.1 mIU/mL (NL = 2 to 17); testosterone, 21.0 ng/dL (NL = 8 to 94); total serum calcium, 9.4 mg/dL, (NL = 8.5 to 10.8); serum phosphorous, 3.2 mg/dL (NL = 2.5 to 4.6); alkaline phosphatase, 66 U/L (NL = 25 to 140). Fertility and Sterility
Pituitary reserve was tested using insulin and thyrotropin-releasing hormone (TRH) stimulation tests. After intravenous (IV) administration of 0.1 U /kg of regular insulin, the blood glucose dropped from 76 to 22 mg/dL by 30 minutes, accompanied by satisfactory growth hormone «0.1 to 29 ng/mL) and cortisol (10.7 to 40 Jlg/dL) elevations. After an IV dose of 500 Jlg synthetic TRH (Thypinone; Abbott Laboratories, Chicago, IL), thyroidstimulating hormone rose from 1.3 to 26.1 JlU/mL by 30 minutes. Prolactin, initially immeasurable at <0.1 ng/mL, did not change over the 120 minutes of observation (Fig. 1). A gadolinium-enhanced, magnetic resonance imaging scan of the brain revealed no abnormalities. DISCUSSION
This patient demonstrated isolated deficiency of PRL, by laboratory and clinical criteria. Serum concentrations of all other pituitary hormones were within normal limits, as were insulin and TRH . stimulation, tests of pituitary function and reserve. The successful induction of ovulation by CC indicated a functional hypothalamic-pituitary-ovarian aXIS.
The normal calcium, phosphorous, and alkaline phosphatase values ruled out pseudohypoparathyroidism. This condition has been associated with hypoprolactinemia, likely by lack of responsivity of the lactotrophs to parathormone, which has been shown to increase plasma PRL in normal adults (5). Although studies have demonstrated PRL to be necessary for maintenance of luteal function in animals (6), evidence for a physiological role in normal human ovulation is not clear. Indeed, ovulation has been induced and luteal function maintained in hypophysectomized women, and hypoprolactinemia is not generally believed to represent a clinical problem. Turkington (3) described two patients unable to lactate who had PRL levels undetectable by bioassay «2 ng/mL) and failed to respond to chlorpromazine, perphenazine, and alpha-methyl-dopa, pharmacological agents that normally elevate PRL levels. Both conceived without medical therapy. Kauppila et al. (4) reported a woman with puerperal alactogenesis who, despite undetectable immunoactive serum PRL measurements «2 ng/mL), had two normal. pregnancies that were conceived without benefit of ovulation inducing medications. Prolactin determinations in pregnancy, normally 100 to 300 ng/mL in the third trimester ranged from Vol. 58, No.5, November 1992
30
o
15
30
45 60 TIME (MIN)
90
120
Figure 1 Thyrotropin-releasing hormone stimulation test. Synthetic TRH, 500 Ilg, administered at 0 minutes.
4.5 to 7.8 ng/mL. Despite having conceived without medication on two occasions, serial studies of menstrual cycles disclosed abnormalities. Ovulation was delayed, with the LH surge taking place between the 18th and 21st days, and the luteal phase was short, with low progesterone (P) levels. The same group (1) studied the effect of hypoprolactinemia induced by bromocriptine administered in a randomized, placebo-controlled manner in 32 in vitro fertilization patients treated with CC-hMG for ovulation augmentation. The women treated with bromocriptine had shorter luteal phases and lower luteal phase P levels. The suggestion that hypoprolactinemia affected luteal phase function in these patients is intriguing, but the diagnosis, treatment, and even clinical significance of luteal phase deficiency is in itself the subject of ongoing controversy. The fact that they conceived and experienced normal pregnancies without luteal phase support points to a lack of clinical significance of the luteal deficiency in these patients, even in light of a possible mild ovulatory disturbance related to the hypoprolactinemia. It is impossible to state with certainty whether the present patient's oligo-ovulation, one of the most common clinical problems faced by the reproductive endocrinologist, was related to her hypoprolactinemia. Indeed, from a pragmatic clinical point, it is moot. In light of the data relating drug-induced hypoprolactinemia to ovulatory disturbances, however, it seems prudent to maintain the PRL level in the normal range when bromocriptine is used in the treatment of hyperprolactinemic ovulatory dysfunction. SUMMARY
A 36-year-old woman, with lifelong oligomenorrhea and immeasurable serum PRL levels, conceived Falk
Communications-in-brief
1061
and had normal deliveries after ovulation induction with CC. Alactogenesis followed both deliveries. Evaluation of other pituitary hormones were within normal limits, and attempted stimulation of PRL levels by TRH was unsuccessful. The clinical significance of isolated hypoprolactinemia is discussed. Key Words: Hypoprolactinemia, alactogenesis, oligomenorrhea. REFERENCES 1. Kauppila A, Martikainen H, Puistola U, Reinilii M, Riinnberg
L. Hypoprolactinemia and ovarian function. Fertil Steril 1988;49:437-41.
1062
Falk
Communications-in-brief
2. Judd S. The neuroendocrinology of reproduction. In: Shearman RP, editor. Clinical reproductive endocrinology. Edinburgh: Churchill-Livingstone, 1985:1-37. 3. Turkington RW. Phenothiazine stimulation test for prolactin reserve: the syndrome of isolated prolactin deficiency. J Clin Endocrinol Metab 1972;34:247-9. 4. Kauppila A, Chatelain P, Kirkinen P, Kivinen S, Ruokonen A. Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 1987;64:309-12. 5. Isaac R, Merceron RE, Caillens G, Raymond JP, Ardaillou R. Effect of parathyroid hormone on plasma prolactin in man. J Clin Endocrinol Metab 1978;47:18-23. 6. Denamur R, Martinet J, Short RV. Pituitary control of the ovine corpus luteum. J Reprod Fertil 1973;32:207-20.
Fertility and Sterility
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright © 1992 The American Fertility Society
Isolated prolactin deficiency: a case report
Richard J, Falk, M.D.* Division of Reproductive Endocrinology and Infertility, Columbia Hospital for Women, Washington, D.C.
Hypoprolactinemia consequent to hypophysectomy or pharmacological suppression has been reported to adversely affect the luteal phase of the menstrual cycle (1). Although these are nonphysiological states that could as well affect the ovulatory process by other mechanisms, some authorities have concluded that a minimal amount of the hormone (1 to 3 ng/mL) is necessary for normal ovulatory function (2). An isolated prolactin (PRL) deficiency, unaccompanied by pharmacological or surgical perturbations, could shed light on the role of the hormone on ovulation, but the condition is uncommon, with only three such patients having been reported (3, 4). The present case report extends this small data base by describing a patient with isolated PRL deficiency, alactogenesis, and irregular ovulation. CASE REPORT
The patient is a 36-year-old gravida 2, para 2, who had experienced normal childhood and adolescent development. After spontaneous menarche at age 13, her menses were grossly irregular, for which oral contraceptives were started at age 16. Desirous of pregnancy at age 30, the medication was discontinued, and she resumed her pretreatment oligomenorrheic pattern. Physical examination at that time revealed a woman with normal secondary sex characteristics. A serum PRL of <0.1 ,ug/L ruled out hyperprolactinemia as a cause of the ovulatory disturbance, and after successful induction of withdrawal bleeding by administration of medroxyprogesterone acetate (MPA, Provera; The Upjohn Co, Kalamazoo, MI), 10 mg/d for 7 days, she was treated
Received March 27, 1992; revised and accepted July 7, 1992.
* Reprint requests: Richard J. Falk, M.D., Division of Reproductive Endocrinology and Infertility, Columbia Hospital for Women, 2440 M Street, NW, Suite 401, Washington, D,C. 20037.
1060
Falk
Communications-in-brief
with clomiphene citrate (CC, Clomid; Marion Merrell Dow, Inc., Cincinnati, OH). At a dose of 50 mg/d for 5 days, basal temperatures remained monophasic, and the CC was increased to 100 mg/d. Although a thermal shift occurred at this dose, the luteal phase was short «8 days), and the medication was increased to 150 mg/d for 5 days. She conceived after two cycles of this regimen and had an uneventful pregnancy, culminating in a vaginal delivery with neither intrapartum nor postpartum complications. The puerperium was characterized by alactogenesis. She remained anovulatory, and oral contraception was reinstituted after several months. Three years later (February 1989), she was again successfully treated with CC, 150 mg/d, and subsequent to the uncomplicated birth of her second child, she again failed to establish lactation. After remaining amenorrheic for 1 year, with occasional MPA-induced withdrawal bleeding, she was referred to the endocrine service for evaluation. There was no family history of problems with lactation, irregular or absent menses, infertility, or musculoskeletal abnormalities. Physical examination revealed a well-developed woman, 165 cm tall, 61.25 kg, with a normal female body habitus and hair distribution. Her breasts were Tanner stage V, without masses or nipple discharge. The uterus was of normal size, shape, and consistency, and no adnexal masses were present. Hormone assays, performed by commercially available radioimmunoassay, were as follows: serum PRL, <0.1 ,ug/L (repeated) (normal limits [NL] = 1 to 18); estradiol, 16 and 29 pg/mL (NL = >40); follicle-stimulating hormone, 3.3 mIU /mL (NL = 2 to 9); luteinizing hormone (LH), 6.1 mIU/mL (NL = 2 to 17); testosterone, 21.0 ng/dL (NL = 8 to 94); total serum calcium, 9.4 mg/dL, (NL = 8.5 to 10.8); serum phosphorous, 3.2 mg/dL (NL = 2.5 to 4.6); alkaline phosphatase, 66 U/L (NL = 25 to 140). Fertility and Sterility
Pituitary reserve was tested using insulin and thyrotropin-releasing hormone (TRH) stimulation tests. After intravenous (IV) administration of 0.1 U /kg of regular insulin, the blood glucose dropped from 76 to 22 mg/dL by 30 minutes, accompanied by satisfactory growth hormone «0.1 to 29 ng/mL) and cortisol (10.7 to 40 Jlg/dL) elevations. After an IV dose of 500 Jlg synthetic TRH (Thypinone; Abbott Laboratories, Chicago, IL), thyroidstimulating hormone rose from 1.3 to 26.1 JlU/mL by 30 minutes. Prolactin, initially immeasurable at <0.1 ng/mL, did not change over the 120 minutes of observation (Fig. 1). A gadolinium-enhanced, magnetic resonance imaging scan of the brain revealed no abnormalities. DISCUSSION
This patient demonstrated isolated deficiency of PRL, by laboratory and clinical criteria. Serum concentrations of all other pituitary hormones were within normal limits, as were insulin and TRH . stimulation, tests of pituitary function and reserve. The successful induction of ovulation by CC indicated a functional hypothalamic-pituitary-ovarian aXIS.
The normal calcium, phosphorous, and alkaline phosphatase values ruled out pseudohypoparathyroidism. This condition has been associated with hypoprolactinemia, likely by lack of responsivity of the lactotrophs to parathormone, which has been shown to increase plasma PRL in normal adults (5). Although studies have demonstrated PRL to be necessary for maintenance of luteal function in animals (6), evidence for a physiological role in normal human ovulation is not clear. Indeed, ovulation has been induced and luteal function maintained in hypophysectomized women, and hypoprolactinemia is not generally believed to represent a clinical problem. Turkington (3) described two patients unable to lactate who had PRL levels undetectable by bioassay «2 ng/mL) and failed to respond to chlorpromazine, perphenazine, and alpha-methyl-dopa, pharmacological agents that normally elevate PRL levels. Both conceived without medical therapy. Kauppila et al. (4) reported a woman with puerperal alactogenesis who, despite undetectable immunoactive serum PRL measurements «2 ng/mL), had two normal. pregnancies that were conceived without benefit of ovulation inducing medications. Prolactin determinations in pregnancy, normally 100 to 300 ng/mL in the third trimester ranged from Vol. 58, No.5, November 1992
30
o
15
30
45 60 TIME (MIN)
90
120
Figure 1 Thyrotropin-releasing hormone stimulation test. Synthetic TRH, 500 Ilg, administered at 0 minutes.
4.5 to 7.8 ng/mL. Despite having conceived without medication on two occasions, serial studies of menstrual cycles disclosed abnormalities. Ovulation was delayed, with the LH surge taking place between the 18th and 21st days, and the luteal phase was short, with low progesterone (P) levels. The same group (1) studied the effect of hypoprolactinemia induced by bromocriptine administered in a randomized, placebo-controlled manner in 32 in vitro fertilization patients treated with CC-hMG for ovulation augmentation. The women treated with bromocriptine had shorter luteal phases and lower luteal phase P levels. The suggestion that hypoprolactinemia affected luteal phase function in these patients is intriguing, but the diagnosis, treatment, and even clinical significance of luteal phase deficiency is in itself the subject of ongoing controversy. The fact that they conceived and experienced normal pregnancies without luteal phase support points to a lack of clinical significance of the luteal deficiency in these patients, even in light of a possible mild ovulatory disturbance related to the hypoprolactinemia. It is impossible to state with certainty whether the present patient's oligo-ovulation, one of the most common clinical problems faced by the reproductive endocrinologist, was related to her hypoprolactinemia. Indeed, from a pragmatic clinical point, it is moot. In light of the data relating drug-induced hypoprolactinemia to ovulatory disturbances, however, it seems prudent to maintain the PRL level in the normal range when bromocriptine is used in the treatment of hyperprolactinemic ovulatory dysfunction. SUMMARY
A 36-year-old woman, with lifelong oligomenorrhea and immeasurable serum PRL levels, conceived Falk
Communications-in-brief
1061
and had normal deliveries after ovulation induction with CC. Alactogenesis followed both deliveries. Evaluation of other pituitary hormones were within normal limits, and attempted stimulation of PRL levels by TRH was unsuccessful. The clinical significance of isolated hypoprolactinemia is discussed. Key Words: Hypoprolactinemia, alactogenesis, oligomenorrhea. REFERENCES 1. Kauppila A, Martikainen H, Puistola U, Reinilii M, Riinnberg
L. Hypoprolactinemia and ovarian function. Fertil Steril 1988;49:437-41.
1062
Falk
Communications-in-brief
2. Judd S. The neuroendocrinology of reproduction. In: Shearman RP, editor. Clinical reproductive endocrinology. Edinburgh: Churchill-Livingstone, 1985:1-37. 3. Turkington RW. Phenothiazine stimulation test for prolactin reserve: the syndrome of isolated prolactin deficiency. J Clin Endocrinol Metab 1972;34:247-9. 4. Kauppila A, Chatelain P, Kirkinen P, Kivinen S, Ruokonen A. Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 1987;64:309-12. 5. Isaac R, Merceron RE, Caillens G, Raymond JP, Ardaillou R. Effect of parathyroid hormone on plasma prolactin in man. J Clin Endocrinol Metab 1978;47:18-23. 6. Denamur R, Martinet J, Short RV. Pituitary control of the ovine corpus luteum. J Reprod Fertil 1973;32:207-20.
Fertility and Sterility