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Pituitary sulfated hCG
Pituitary sulfated hCG Laurence A. Cole USA hCG Reference Service, Angel Fire, NM, USA
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Numerous older publications from the 1960s, 1970s, and 1980s suggested bacteria, crabs, and other unlikely sources to explain detection of hCG outside of pregnancy [1 8]. We now have a better understanding of the various sources of hCG when a person is not pregnant. This is explained in Chapter 28, Positive hCG Tests: Causes Other than Pregnancy, as quiescent gestational trophoblastic disease, as false-positive hCG assays, and as sulfated pituitary hCG. From this chapter we understand that men and women can have positive hCG tests because of circulating heterophilic or interfering antibodies. These cause false-positive hCG results and explain some of the strange findings in non-pregnant individuals [9 11]. We also now know that men and women with cancer normally produce the total hCG assay immunoreactive free β-subunit of hCG [12 14]. Here we examine the evidence that shows that the pituitary gland normally produces sulfated hCG during the menstrual cycle and in menopause [15 19]. This is a further cause of positive hCG results in non-pregnant individuals. It has now been 33 years since hCG production was first demonstrated to come from the pituitary gland [20]. Since then, more than 40 publications have confirmed pituitary production and described how low levels of hCG (,3 mIU/ml) accompany luteinizing hormone (LH) during the menstrual cycle [15 29]. In amenorrhea or menopause, and partially in perimenopause, the ovary fails to provide estrogen to feed back to the hypothalamus to inhibit and control gonadotropin-releasing hormone (GnRH) production (Figure 16.1). This leads to GnRH pulses constantly stimulating the pituitary gonadotrope cells, to increased production of LH and follicle-stimulating hormone, and to the increased incidental production of human chorionic gonadotropin (,1.0 to 33.6 mIU/ml) (Figure 16.1). It is thought that the increased production of hCG may be incidental because the single LH β-subunit gene of chromosome 19 is buried in the middle of eight parallel hCG β-subunit genes. Excess common α-subunit made in the pituitary combines with the hCG β-subunit. It is possible that the increased levels of hCG (extremely low concentrations) may result from the incidental potent action of GnRH on that group of eight hCGβ genes and one LHβ gene in menopausal women. As such, elevated levels of hCG (.1 mIU/ml) may be evident in all women with amenorrhea or menopause (age older than 48), in women after bilateral salpingooophorectomy (BSO), and in women during oligomenorrhea in perimenopause [15 18,21,24 29]. In medical practice, a positive hCG test result prior to menopause suggests pregnancy or gestational trophoblastic disease [23,24,27,28]. Positive hCG test results in perimenopausal and menopausal women, however, suggest elevated pituitary hCG (,1.0 to 33.6 mIU/ml). Human Chorionic Gonadotropin (hCG). DOI: http://dx.doi.org/10.1016/B978-0-12-800749-5.00016-X © 2015 Elsevier Inc. All rights reserved.
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Figure 16.1 Endocrine feedback pathway linking the ovary, the hypothalamus, and anterior pituitary (at base of brain) in women.
Today, testing for pregnancy is routinely performed before surgical procedures, before imaging procedures, before administration of certain medications that might harm a fetus, and with admission to emergency departments. When hCG is detected, all planned procedures, whether critical or non-critical, are halted pending investigation of pregnancy and the source of hCG, seemingly regardless of patient age or menopausal status. After excluding regular and ectopic pregnancies, most nonpregnant positive hCG cases, regardless of age or menopausal status, are referred to gynecologic oncologists. Numerous older obstetrics and gynecology textbooks state that the only source of hCG, if pregnancy and ectopic pregnancy have been eliminated, is choriocarcinoma or cancer. Many physicians still adhere to these guidelines, which generally leads to needless hysterectomies or unnecessary chemotherapy in menopausal patients naturally producing pituitary hCG. Studies show that, extremely rarely, cases of positive hCG outside of pregnancy involve a malignancy or choriocarcinoma [30 34]. In most cases it is just pituitary hCG.
Pituitary sulfated hCG
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Sixty million women are now in perimenopause or menopause in the United States. Considering the frequency of hCG testing before surgery, at the emergency department, before administration of certain drugs, and before X-rays, many of these 60 million have to experience the stress and alarm of a non-pregnancy positive hCG test. Here we carefully consider all aspects of pituitary hCG, a key form of hCG present in menopausal women. We examine its structure, its biological function, and its occurrence.
16.1
Structure of pituitary sulfated hCG
Pituitary hCG has an amino acid structure identical to placental hCG [25]. It is unique, however, in having a variable portion of sulfated oligosaccharides [25]. The sulfate groups are attached to N-acetylgalactosamine residues, which replace galactose and sialic acid residues in N-linked and O-linked oligosaccharides (Figure 16.2). As published, the β-subunit of pituitary hCG has 2.7 mole/mole oligosaccharides terminating in sulfate groups and 4.6 mole/mole oligosaccharides terminating in sialic acid groups, or 37% sulfation [25]. The α-subunit of pituitary hCG has 0.8 mole/mole oligosaccharides terminating in sulfate and 1.7 mole/mole oligosaccharides terminating in sialic acid groups, or 32% sulfation. Sulfated hCG is less acidic than sialylated or normal pregnancy hCG. As such, it has a lower circulating half-life (20 h versus 36 h) and 50% of the biological activity of normal pregnancy hCG [25].
16.2
Biological function of pituitary sulfated hCG
The USA hCG Reference Service recently examined more than 8300 urine samples from women with normal menstrual periods [18]. Low concentrations (.1 mIU/ml) of hCG were detectable at the time of the mid-cycle LH peak in 232 of 277 menstrual cycles [18]. The mean hCG level at the time of LH peak was 1.54 6 0.90 mIU/ml and the range was ,1.0 9.2 mIU/ml. Considering the mean and the distribution of the range of hCG values, it is logical to assume that the 45 of 277 menstrual cycles in which hCG was not detected produced lower hCG concentrations (.1 mIU/ml)—too low to be detected by the assay used (the Siemens Immulite 1000 assay, sensitivity $1.0). It was inferred that these low concentrations of hCG (,1.0 9.2 mIU/ml) supplement LH during all human menstrual cycles and are part of normal physiology. As shown by Odell and Griffin [35,36], using an ultra-sensitive sandwich assay for hCG, pituitary hCG is produced at very low levels (0.01 mIU/ml) in healthy men, with a wide range from 0.03 to 1.7 mIU/ml [35,36]. Pituitary hCG was detected in women in pulses of the luteal and follicular phases of the menstrual cycle that paralleled LH levels [35,36]. Injections of GnRH were shown to directly promote circulating pituitary hCG levels in men and women, just as it similarly
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Figure 16.2 The N-linked and O-linked sugar structures on pituitary sulfated hCG.
promoted LH levels [35,36]. It is inferred that pituitary hCG supplements pituitary LH in healthy men and women [18,25,36]. It is yet unknown whether there is a specific function for pituitary hCG, independent of LH, during the menstrual cycle. Pituitary hCG could have functions separate from those of LH. But even if pituitary hCG has no specific function, there is a natural explanation for its production. There is a single LH β-subunit gene buried among the eight back-to-back hCG β-subunit genes on human chromosome 19 [37]. hCG and LH share a single common α-subunit. It is possible that a small amount of hCGβ is promoted by GnRH along with specific LH β-subunit stimulation in pituitary gonadotrope cells during normal menstrual cycle physiology in women and in men.
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LH has multiple functions during the LH peak and ovulation period. We know that both LH and hCG act on the LH/hCG receptor to promote progesterone production by corpus luteum cells [26,29,38]. We assume that LH and hCG act on the same receptor on follicles. As established, with the appearance of an LH/hCG receptor on granulosa cells of the Graafian follicle or primary follicle, LH first promotes follicular growth [39,40], and then it stimulates diploid cell meiosis [41,42]. LH causes the follicle to form a stigma or protrusion [43], and then it promotes collagenase production to degrade and penetrate the stigma [43,44]. The penetration of the stigma causes bursting of the follicle (ovulation) to occur. LH then acts to differentiate the burst or ovulated follicle into a corpus luteum [45,46]. It is not clear whether hCG just incidentally assists LH in each of these five steps or if it has specific functions of its own in one or more of these steps. Consider that the mean hCG at the time of the LH peak is 1.54 6 0.90 mIU/ml [18]. Consider that the mean LH, at the time of peak, is 70 90 mIU/ml or 50-fold greater. Then, consider that the mean biological activity of pituitary hCG is approximately 50-times that of hCG. The 50-times greater biological activity is balanced by the 50-fold lesser concentration. As such, pituitary hCG and LH probably contribute as equal partners to ovulation at the time of LH peak. Similarly, the mass of hCG in an individual woman’s or man’s pituitary gland is 0.5 1.1 μg/gland. This is approximately 25- to 50-fold less than the mass of LH in a woman’s pituitary gland [29]. Publications show that pituitary hCG has approximately half the biological activity in promoting progesterone production of placental hCG [25]. In conclusion, the pituitary hCG seems to parallel LH in an approximately 50 bioactivity:50 bioactivity relationship during the course of the menstrual cycle in women and in men. The saying that LH promotes ovulation may not be correct.
16.3
Occurrence of pituitary sulfated hCG
As shown by the USA hCG Reference Service with more than 8300 urine samples, women produce 1.54 6 0.90 mIU/ml (mean 6 standard deviation) of pituitary hCG during the LH peak of the normal menstrual cycle [18]. Odell and Griffin showed, in contrast, that a miniscule level of 0.01 mIU/ml (average) pituitary hCG is detectable in all men [35,36]. Similar miniscule levels of pituitary hCG are detected during the luteal and follicular phase of the menstrual cycle [35,36]. Extremely low levels of hCG can be detected in healthy men and in women during the luteal and follicular phases of menstrual cycle. These tiny concentrations are close to or below the detection limits of most laboratory hCG/pregnancy assays. Rarely do these tiny levels cause alarm regarding possible pregnancy or halt scheduled surgeries or necessary procedures. During menopause (age older than 42) and as early as perimenopause (age older than 38), the ovary partially or completely fails, thus reducing or halting production of progestagens and estrogens. Similarly, if a woman receives a bilateral oophorectomy, then production of progestagens and estrogens will halt and she will be in a
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state of menopause. Estrogens modulate GnRH pulses by the hypothalamus. In the absence or reduced presence of estrogen, GnRH pulses go wild and become as frequent as possible. This leads to highly increased serum LH and follicle-stimulating hormone (FSH) concentrations. Pituitary hCG is increased significantly as well. In menopausal women, the mean pituitary hCG level in serum is 9.66 6 6.52 mIU/ml and the range is 1.3 33.6 mIU/ml [19]. As defined, perimenopausal women are still fertile but have increased FSH levels (.30 mIU/ml) [17] and oligomenorrhea (extremely variable menstrual periods) [15]. Menopausal woman have amenorrhea or no menstrual cycle. Oophorectomy and primary amenorrhea induce the onset of menopause at an early age. The USA hCG Reference Service’s experience with 103 cases is presented in Table 16.1. As shown, the mean serum concentration of pituitary hCG was 5.5 6 3.2 mIU in perimenopausal women (range 1.4 12 mIU/ml), 11.0 6 6.3 mIU/ml in menopausal women (range 2.1 32.9 mIU/ml), and 9.8 6 9.5 mIU/ml in women with a history of oophorectomy or primary amenorrhea (range 1.8 33.6 mIU/ml). A significant difference was observed between perimenopause and menopause cases (P 5 0.000064), and between perimenopause and oophorectomy plus primary amenorrhea cases (P 5 0.029). The USA hCG Reference Service consults on numerous pituitary hCG cases each year (Table 16.1). These cases seem to mostly derive from routine hCG testing performed on women before surgery, X-ray procedures, and emergency department visits. It appears to the USA hCG Reference Service that these services wrongly concluded from a positive hCG test that these menopausal women were pregnant. Women are routinely tested for pregnancy by ultrasound, are tested further for ectopic pregnancy by ultrasound and other methods, are administered methotrexate to eliminate ectopic pregnancy, and, finally, are referred to an oncologist or gynecologic oncologist for cancer investigation. All too often these women undergo an unnecessary hysterectomy or chemotherapy when hCG levels do not disappear [15,16]. More than 40 publications have described the normality of pituitary hCG in menopausal women, but it appears that physicians either have not read these publications or they cannot believe that a positive hCG test can mean anything but pregnancy. Time and again, after excluding cancer, choriocarcinoma, and other possible explanations (see Chapter 28), we conclude that a patient has pituitary hCG (Table 16.1). These are the kinds of cases that get referred to the USA hCG Reference Service. We know of four cases in which menopausal women were waiting years for a renal transplant. Finally, a matching kidney became available and, when they entered the hospital for the transplantation, they were administered the hCG test. It was positive. Even though, based on age, it was not physically possible for them to be pregnant their transplant procedures were canceled and the kidneys were given to other patients. All because of the positive hCG test. The USA hCG Reference Service has no specific assay for sulfated pituitary hCG because there is no known specific antibody that only detects sulfated pituitary hCG. We simply exclude other possibilities like gestational trophoblastic disease, familial hCG syndrome, quiesced gestational trophoblastic disease, and cancer. Hyperglycosylated hCG (hCG-H) is not produced by the pituitary (Table 16.1).
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Table 16.1 The USA hCG Reference Service experience with 103 woman demonstrated to be producing pituitary hCG Case #, Age
hCG (mIU/ml)
hCG-H (mIU/ml)
History
A. Perimenopausal woman in oligomenhorea Case 455, Age 38 Case 339, Age 39 Case 194, Age 39 Case 199, Age 39 Case 563, Age 40 Case 150, Age 40 Case 561, Age 40 Case 36, Age 40 Case 216, Age 40 Case 427, Age 40 Case 422, Age 42 Case 442, Age 42 Case 377, Age 43 Case 421, Age 43 Case 317, Age 44 Case 305, Age 44 Case 410, Age 44 Case 257, Age 44 Case 173, Age 46 Case 3, Age 46 Case 313, Age 46 Case 506, Age 46 Case 534, Age 47
2.0 2.0 5.8 2.8 6.0 7.6 10.1 12.0 4.4 11.6 8.3 7.2 8.4 3.8 3.2 4.2 9.2 2.2 3.0 3.3 3.7 5.0 1.4
23 cases, Mean
5.5 6 3.2 Range 1.4 12
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
B. Menopausal women experiencing amenorrhea Case 331, Age 42 Case 538, Age 42 Case 397, Age 43 Case 489, Age 43 Case 499, Age 44 Case 17, Age 45 Case 432, Age 47 Case 187, Age 48 Case 350, Age 48 Case 450, Age 48 Case 328, Age 48 Case 300, Age 49 Case 406, Age 49 Case 533, Age 49 Case 540, Age 49
20.0 12.9 16.1 12.7 6.4 7.2 10.6 12.2 4.1 7.7 6.8 2.1 19.2 7.7 9.9
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 (Continued)
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Table 16.1
Human Chorionic Gonadotropin (hCG)
(Continued)
Case #, Age
hCG (mIU/ml)
hCG-H (mIU/ml)
Case 22, Age 50 Case 412, Age 50 Case 425, Age 50 Case 306, Age 50 Case 376, Age 51 Case 169, Age 51 Case 191, Age 51 Case 201, Age 51 Case 79, Age 51 Case 206, Age 51 Case 411, Age 51 Case 413, Age 51 Case 434, Age 51 Case 564, Age 51 Case 21, Age 52 Case 32, Age 52 Case 151, Age 52 Case 193, Age 52 Case 143, Age 52 Case 344, Age 52 Case 469, Age 52 Case 164, Age 53 Case 183, Age 53 Case 192, Age 53 Case 20, Age 53 Case 90, Age 53 Case 329, Age 53 Case 478, Age 53 Case 49, Age 54 Case 336, Age 54 Case 517, Age 54 Case 467, Age 54 Case 476, Age 54 Case 127, Age 55 Case 320, Age 55 Case 565, Age 55 Case 445, Age 55 Case 465, Age 55 Case 269, Age 55 Case 357, Age 55 Case 498, Age 55 Case 115, Age 56 Case 188, Age 57 Case 34, Age 57 Case 162, Age 59
16.2 7.5 12.5 7.7 9.8 7.4 13.7 4.3 13.7 12.3 8.1 4.1 14.6 7.3 4.7 11.0 9.0 10.2 10.6 14.5 7.5 27.2 5.9 10.6 6.0 10.4 7.0 9.3 6.1 6.7 39.0 6.0 12.1 5.3 8.0 8.2 9.2 4.6 9.6 14.2 11.5 7.3 7.9 14.9 15.6
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
History
(Continued)
Pituitary sulfated hCG
Table 16.1
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(Continued)
Case #, Age
hCG (mIU/ml)
hCG-H (mIU/ml)
Case 429, Age 59 Case 34, Age 60 Case 514, Age 61 Case 517, Age 62 Case 543, Age 66 Case 548, Age 68 Case 182, Age 69 Case 18, Age 70 Case 428, Age 54
16.1 32.9 28.5 15.2 17.1 2.5 4.5 31.5 16
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
69 cases, Mean
11.4 6 7.1 Range 2.1 39.0
History
C. Bilateral oophorectomy and primary amennhorea Case 444, Age 34 Case 349, Age 35 Case 519, Age 35 Case 454, Age 36 Case 460, Age 37 Case 322, Age 40 Case 468, Age 29 Case 415, Age 42 Case 319, Age 28 Case 319, Age 28 Case 471, Age 34
3.2 11.5 2.3 3.9 6.9 1.8 6.1 19.4 12.7 33.6 6.4
11 cases. Mean
9.8 6 9.5 Range 1.8 33.6
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
Oophorectomy Oophorectomy Oophorectomy Oophorectomy Oophorectomy Oophorectomy Amenorrhea Amenorrhea Oophorectomy Oophorectomy Oophorectomy
There are, however, two other tests that are invaluable. The first test is the FSH test. As shown by Gronowski et al. [17], increased serum FSH of .30 mIU/ml illustrates perimenopause and menopause, or a lack of sufficient steroid feedback to the hypothalamus. An FSH level of .30 mIU/ml means that there is likely to be elevated pituitary hCG present. In the experience of the USA hCG Reference Service, an FSH test ( .30 mIU/ml) correctly predicated pituitary hCG in 29 of 30 cases tested. The second test involves treating patients with a high-estrogen oral contraceptive pill for 3 weeks, which suppresses pituitary hCG and proves whether the hCG is, in fact, from a pituitary origin [15,16,24,28]. These two methods make it easy to prove pituitary hCG is the source of circulating hCG. We emphasize again, however, that production of pituitary hCG in menopause is normal and natural, and it does not mean pregnancy or cancer. Hospitals need to start using the FSH test along with the hCG tests when evaluating women before surgery. If the FSH is .30 mIU/ml, then they need to consider that a positive hCG result is attributable to pituitary hCG. All pregnancies will still be identified by the hCG test.
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[38] Lei ZM, Reshef E, Rao CV. The expression of human chorionic gonadotropin/ luteinizing hormone receptors in human endometrial and myometrial blood vessels. J Clin Endocrinol Metab 1992;75:651 9. [39] Gougeon A. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1986;1:81 7. [40] Bogovich K, Richards JS, Reichert Jr LE. Obligatory role of luteinizing hormone (LH) in the initiation of preovulatory follicular growth in the pregnant rat: specific effects of human chorionic gonadotropin and follicle-stimulating of hormone on LH receptors and steroidogenesis in theca, granulosa, and luteal cells. Endocrinology 1981;109:860 7. [41] Motola S, Popliker M, Tsafriri A. Are steroids obligatory mediators of LH/hCG triggered resumption of meiosis in mammals? Biol Reprod 2007;77:167 8. [42] Hegele-Hartung C, Gru¨tznera M, Lessla M, Grøndahl C, Ottesen JL, Bra¨nnstro¨m M. Activation of meiotic maturation in rat oocytes after treatment with follicular fluid meiosis-activating sterol in vitro and ex vivo. Biol Reprod 2001;64:418 24. [43] Robkera RL, Russella DL, Yoshiokab S, Sharmaa SC, Lydona JP, O’Malleya BW, et al. Ovulation: a multi-gene, multi-step process. Steroids 2000;65:559 70. [44] Butler TA, Zhu C, Mueller RA, Fuller GC, Lemaire WJ, Woessner Jr JF. Inhibition of ovulation in the perfused rat ovary by the synthetic collagenase inhibitor SC 44463. Biol Reprod 1991;44:1183 8. [45] Acosta JT, Miyamoto A. Vascular control of ovarian function: ovulation, corpus luteum formation and regression. Anim Reprod Sci 2004;82 83:127 40. [46] Nalbandov AV, Bahr JM. Ovulation, corpus luteum formation, and steroidogenesis. Basic Life Sci 1974;4:399 407.
16
Numerous older publications from the 1960s, 1970s, and 1980s suggested bacteria, crabs, and other unlikely sources to explain detection of hCG outside of pregnancy [1 8]. We now have a better understanding of the various sources of hCG when a person is not pregnant. This is explained in Chapter 28, Positive hCG Tests: Causes Other than Pregnancy, as quiescent gestational trophoblastic disease, as false-positive hCG assays, and as sulfated pituitary hCG. From this chapter we understand that men and women can have positive hCG tests because of circulating heterophilic or interfering antibodies. These cause false-positive hCG results and explain some of the strange findings in non-pregnant individuals [9 11]. We also now know that men and women with cancer normally produce the total hCG assay immunoreactive free β-subunit of hCG [12 14]. Here we examine the evidence that shows that the pituitary gland normally produces sulfated hCG during the menstrual cycle and in menopause [15 19]. This is a further cause of positive hCG results in non-pregnant individuals. It has now been 33 years since hCG production was first demonstrated to come from the pituitary gland [20]. Since then, more than 40 publications have confirmed pituitary production and described how low levels of hCG (,3 mIU/ml) accompany luteinizing hormone (LH) during the menstrual cycle [15 29]. In amenorrhea or menopause, and partially in perimenopause, the ovary fails to provide estrogen to feed back to the hypothalamus to inhibit and control gonadotropin-releasing hormone (GnRH) production (Figure 16.1). This leads to GnRH pulses constantly stimulating the pituitary gonadotrope cells, to increased production of LH and follicle-stimulating hormone, and to the increased incidental production of human chorionic gonadotropin (,1.0 to 33.6 mIU/ml) (Figure 16.1). It is thought that the increased production of hCG may be incidental because the single LH β-subunit gene of chromosome 19 is buried in the middle of eight parallel hCG β-subunit genes. Excess common α-subunit made in the pituitary combines with the hCG β-subunit. It is possible that the increased levels of hCG (extremely low concentrations) may result from the incidental potent action of GnRH on that group of eight hCGβ genes and one LHβ gene in menopausal women. As such, elevated levels of hCG (.1 mIU/ml) may be evident in all women with amenorrhea or menopause (age older than 48), in women after bilateral salpingooophorectomy (BSO), and in women during oligomenorrhea in perimenopause [15 18,21,24 29]. In medical practice, a positive hCG test result prior to menopause suggests pregnancy or gestational trophoblastic disease [23,24,27,28]. Positive hCG test results in perimenopausal and menopausal women, however, suggest elevated pituitary hCG (,1.0 to 33.6 mIU/ml). Human Chorionic Gonadotropin (hCG). DOI: http://dx.doi.org/10.1016/B978-0-12-800749-5.00016-X © 2015 Elsevier Inc. All rights reserved.
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Figure 16.1 Endocrine feedback pathway linking the ovary, the hypothalamus, and anterior pituitary (at base of brain) in women.
Today, testing for pregnancy is routinely performed before surgical procedures, before imaging procedures, before administration of certain medications that might harm a fetus, and with admission to emergency departments. When hCG is detected, all planned procedures, whether critical or non-critical, are halted pending investigation of pregnancy and the source of hCG, seemingly regardless of patient age or menopausal status. After excluding regular and ectopic pregnancies, most nonpregnant positive hCG cases, regardless of age or menopausal status, are referred to gynecologic oncologists. Numerous older obstetrics and gynecology textbooks state that the only source of hCG, if pregnancy and ectopic pregnancy have been eliminated, is choriocarcinoma or cancer. Many physicians still adhere to these guidelines, which generally leads to needless hysterectomies or unnecessary chemotherapy in menopausal patients naturally producing pituitary hCG. Studies show that, extremely rarely, cases of positive hCG outside of pregnancy involve a malignancy or choriocarcinoma [30 34]. In most cases it is just pituitary hCG.
Pituitary sulfated hCG
153
Sixty million women are now in perimenopause or menopause in the United States. Considering the frequency of hCG testing before surgery, at the emergency department, before administration of certain drugs, and before X-rays, many of these 60 million have to experience the stress and alarm of a non-pregnancy positive hCG test. Here we carefully consider all aspects of pituitary hCG, a key form of hCG present in menopausal women. We examine its structure, its biological function, and its occurrence.
16.1
Structure of pituitary sulfated hCG
Pituitary hCG has an amino acid structure identical to placental hCG [25]. It is unique, however, in having a variable portion of sulfated oligosaccharides [25]. The sulfate groups are attached to N-acetylgalactosamine residues, which replace galactose and sialic acid residues in N-linked and O-linked oligosaccharides (Figure 16.2). As published, the β-subunit of pituitary hCG has 2.7 mole/mole oligosaccharides terminating in sulfate groups and 4.6 mole/mole oligosaccharides terminating in sialic acid groups, or 37% sulfation [25]. The α-subunit of pituitary hCG has 0.8 mole/mole oligosaccharides terminating in sulfate and 1.7 mole/mole oligosaccharides terminating in sialic acid groups, or 32% sulfation. Sulfated hCG is less acidic than sialylated or normal pregnancy hCG. As such, it has a lower circulating half-life (20 h versus 36 h) and 50% of the biological activity of normal pregnancy hCG [25].
16.2
Biological function of pituitary sulfated hCG
The USA hCG Reference Service recently examined more than 8300 urine samples from women with normal menstrual periods [18]. Low concentrations (.1 mIU/ml) of hCG were detectable at the time of the mid-cycle LH peak in 232 of 277 menstrual cycles [18]. The mean hCG level at the time of LH peak was 1.54 6 0.90 mIU/ml and the range was ,1.0 9.2 mIU/ml. Considering the mean and the distribution of the range of hCG values, it is logical to assume that the 45 of 277 menstrual cycles in which hCG was not detected produced lower hCG concentrations (.1 mIU/ml)—too low to be detected by the assay used (the Siemens Immulite 1000 assay, sensitivity $1.0). It was inferred that these low concentrations of hCG (,1.0 9.2 mIU/ml) supplement LH during all human menstrual cycles and are part of normal physiology. As shown by Odell and Griffin [35,36], using an ultra-sensitive sandwich assay for hCG, pituitary hCG is produced at very low levels (0.01 mIU/ml) in healthy men, with a wide range from 0.03 to 1.7 mIU/ml [35,36]. Pituitary hCG was detected in women in pulses of the luteal and follicular phases of the menstrual cycle that paralleled LH levels [35,36]. Injections of GnRH were shown to directly promote circulating pituitary hCG levels in men and women, just as it similarly
154
Human Chorionic Gonadotropin (hCG)
Figure 16.2 The N-linked and O-linked sugar structures on pituitary sulfated hCG.
promoted LH levels [35,36]. It is inferred that pituitary hCG supplements pituitary LH in healthy men and women [18,25,36]. It is yet unknown whether there is a specific function for pituitary hCG, independent of LH, during the menstrual cycle. Pituitary hCG could have functions separate from those of LH. But even if pituitary hCG has no specific function, there is a natural explanation for its production. There is a single LH β-subunit gene buried among the eight back-to-back hCG β-subunit genes on human chromosome 19 [37]. hCG and LH share a single common α-subunit. It is possible that a small amount of hCGβ is promoted by GnRH along with specific LH β-subunit stimulation in pituitary gonadotrope cells during normal menstrual cycle physiology in women and in men.
Pituitary sulfated hCG
155
LH has multiple functions during the LH peak and ovulation period. We know that both LH and hCG act on the LH/hCG receptor to promote progesterone production by corpus luteum cells [26,29,38]. We assume that LH and hCG act on the same receptor on follicles. As established, with the appearance of an LH/hCG receptor on granulosa cells of the Graafian follicle or primary follicle, LH first promotes follicular growth [39,40], and then it stimulates diploid cell meiosis [41,42]. LH causes the follicle to form a stigma or protrusion [43], and then it promotes collagenase production to degrade and penetrate the stigma [43,44]. The penetration of the stigma causes bursting of the follicle (ovulation) to occur. LH then acts to differentiate the burst or ovulated follicle into a corpus luteum [45,46]. It is not clear whether hCG just incidentally assists LH in each of these five steps or if it has specific functions of its own in one or more of these steps. Consider that the mean hCG at the time of the LH peak is 1.54 6 0.90 mIU/ml [18]. Consider that the mean LH, at the time of peak, is 70 90 mIU/ml or 50-fold greater. Then, consider that the mean biological activity of pituitary hCG is approximately 50-times that of hCG. The 50-times greater biological activity is balanced by the 50-fold lesser concentration. As such, pituitary hCG and LH probably contribute as equal partners to ovulation at the time of LH peak. Similarly, the mass of hCG in an individual woman’s or man’s pituitary gland is 0.5 1.1 μg/gland. This is approximately 25- to 50-fold less than the mass of LH in a woman’s pituitary gland [29]. Publications show that pituitary hCG has approximately half the biological activity in promoting progesterone production of placental hCG [25]. In conclusion, the pituitary hCG seems to parallel LH in an approximately 50 bioactivity:50 bioactivity relationship during the course of the menstrual cycle in women and in men. The saying that LH promotes ovulation may not be correct.
16.3
Occurrence of pituitary sulfated hCG
As shown by the USA hCG Reference Service with more than 8300 urine samples, women produce 1.54 6 0.90 mIU/ml (mean 6 standard deviation) of pituitary hCG during the LH peak of the normal menstrual cycle [18]. Odell and Griffin showed, in contrast, that a miniscule level of 0.01 mIU/ml (average) pituitary hCG is detectable in all men [35,36]. Similar miniscule levels of pituitary hCG are detected during the luteal and follicular phase of the menstrual cycle [35,36]. Extremely low levels of hCG can be detected in healthy men and in women during the luteal and follicular phases of menstrual cycle. These tiny concentrations are close to or below the detection limits of most laboratory hCG/pregnancy assays. Rarely do these tiny levels cause alarm regarding possible pregnancy or halt scheduled surgeries or necessary procedures. During menopause (age older than 42) and as early as perimenopause (age older than 38), the ovary partially or completely fails, thus reducing or halting production of progestagens and estrogens. Similarly, if a woman receives a bilateral oophorectomy, then production of progestagens and estrogens will halt and she will be in a
156
Human Chorionic Gonadotropin (hCG)
state of menopause. Estrogens modulate GnRH pulses by the hypothalamus. In the absence or reduced presence of estrogen, GnRH pulses go wild and become as frequent as possible. This leads to highly increased serum LH and follicle-stimulating hormone (FSH) concentrations. Pituitary hCG is increased significantly as well. In menopausal women, the mean pituitary hCG level in serum is 9.66 6 6.52 mIU/ml and the range is 1.3 33.6 mIU/ml [19]. As defined, perimenopausal women are still fertile but have increased FSH levels (.30 mIU/ml) [17] and oligomenorrhea (extremely variable menstrual periods) [15]. Menopausal woman have amenorrhea or no menstrual cycle. Oophorectomy and primary amenorrhea induce the onset of menopause at an early age. The USA hCG Reference Service’s experience with 103 cases is presented in Table 16.1. As shown, the mean serum concentration of pituitary hCG was 5.5 6 3.2 mIU in perimenopausal women (range 1.4 12 mIU/ml), 11.0 6 6.3 mIU/ml in menopausal women (range 2.1 32.9 mIU/ml), and 9.8 6 9.5 mIU/ml in women with a history of oophorectomy or primary amenorrhea (range 1.8 33.6 mIU/ml). A significant difference was observed between perimenopause and menopause cases (P 5 0.000064), and between perimenopause and oophorectomy plus primary amenorrhea cases (P 5 0.029). The USA hCG Reference Service consults on numerous pituitary hCG cases each year (Table 16.1). These cases seem to mostly derive from routine hCG testing performed on women before surgery, X-ray procedures, and emergency department visits. It appears to the USA hCG Reference Service that these services wrongly concluded from a positive hCG test that these menopausal women were pregnant. Women are routinely tested for pregnancy by ultrasound, are tested further for ectopic pregnancy by ultrasound and other methods, are administered methotrexate to eliminate ectopic pregnancy, and, finally, are referred to an oncologist or gynecologic oncologist for cancer investigation. All too often these women undergo an unnecessary hysterectomy or chemotherapy when hCG levels do not disappear [15,16]. More than 40 publications have described the normality of pituitary hCG in menopausal women, but it appears that physicians either have not read these publications or they cannot believe that a positive hCG test can mean anything but pregnancy. Time and again, after excluding cancer, choriocarcinoma, and other possible explanations (see Chapter 28), we conclude that a patient has pituitary hCG (Table 16.1). These are the kinds of cases that get referred to the USA hCG Reference Service. We know of four cases in which menopausal women were waiting years for a renal transplant. Finally, a matching kidney became available and, when they entered the hospital for the transplantation, they were administered the hCG test. It was positive. Even though, based on age, it was not physically possible for them to be pregnant their transplant procedures were canceled and the kidneys were given to other patients. All because of the positive hCG test. The USA hCG Reference Service has no specific assay for sulfated pituitary hCG because there is no known specific antibody that only detects sulfated pituitary hCG. We simply exclude other possibilities like gestational trophoblastic disease, familial hCG syndrome, quiesced gestational trophoblastic disease, and cancer. Hyperglycosylated hCG (hCG-H) is not produced by the pituitary (Table 16.1).
Pituitary sulfated hCG
157
Table 16.1 The USA hCG Reference Service experience with 103 woman demonstrated to be producing pituitary hCG Case #, Age
hCG (mIU/ml)
hCG-H (mIU/ml)
History
A. Perimenopausal woman in oligomenhorea Case 455, Age 38 Case 339, Age 39 Case 194, Age 39 Case 199, Age 39 Case 563, Age 40 Case 150, Age 40 Case 561, Age 40 Case 36, Age 40 Case 216, Age 40 Case 427, Age 40 Case 422, Age 42 Case 442, Age 42 Case 377, Age 43 Case 421, Age 43 Case 317, Age 44 Case 305, Age 44 Case 410, Age 44 Case 257, Age 44 Case 173, Age 46 Case 3, Age 46 Case 313, Age 46 Case 506, Age 46 Case 534, Age 47
2.0 2.0 5.8 2.8 6.0 7.6 10.1 12.0 4.4 11.6 8.3 7.2 8.4 3.8 3.2 4.2 9.2 2.2 3.0 3.3 3.7 5.0 1.4
23 cases, Mean
5.5 6 3.2 Range 1.4 12
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
B. Menopausal women experiencing amenorrhea Case 331, Age 42 Case 538, Age 42 Case 397, Age 43 Case 489, Age 43 Case 499, Age 44 Case 17, Age 45 Case 432, Age 47 Case 187, Age 48 Case 350, Age 48 Case 450, Age 48 Case 328, Age 48 Case 300, Age 49 Case 406, Age 49 Case 533, Age 49 Case 540, Age 49
20.0 12.9 16.1 12.7 6.4 7.2 10.6 12.2 4.1 7.7 6.8 2.1 19.2 7.7 9.9
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 (Continued)
158
Table 16.1
Human Chorionic Gonadotropin (hCG)
(Continued)
Case #, Age
hCG (mIU/ml)
hCG-H (mIU/ml)
Case 22, Age 50 Case 412, Age 50 Case 425, Age 50 Case 306, Age 50 Case 376, Age 51 Case 169, Age 51 Case 191, Age 51 Case 201, Age 51 Case 79, Age 51 Case 206, Age 51 Case 411, Age 51 Case 413, Age 51 Case 434, Age 51 Case 564, Age 51 Case 21, Age 52 Case 32, Age 52 Case 151, Age 52 Case 193, Age 52 Case 143, Age 52 Case 344, Age 52 Case 469, Age 52 Case 164, Age 53 Case 183, Age 53 Case 192, Age 53 Case 20, Age 53 Case 90, Age 53 Case 329, Age 53 Case 478, Age 53 Case 49, Age 54 Case 336, Age 54 Case 517, Age 54 Case 467, Age 54 Case 476, Age 54 Case 127, Age 55 Case 320, Age 55 Case 565, Age 55 Case 445, Age 55 Case 465, Age 55 Case 269, Age 55 Case 357, Age 55 Case 498, Age 55 Case 115, Age 56 Case 188, Age 57 Case 34, Age 57 Case 162, Age 59
16.2 7.5 12.5 7.7 9.8 7.4 13.7 4.3 13.7 12.3 8.1 4.1 14.6 7.3 4.7 11.0 9.0 10.2 10.6 14.5 7.5 27.2 5.9 10.6 6.0 10.4 7.0 9.3 6.1 6.7 39.0 6.0 12.1 5.3 8.0 8.2 9.2 4.6 9.6 14.2 11.5 7.3 7.9 14.9 15.6
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
History
(Continued)
Pituitary sulfated hCG
Table 16.1
159
(Continued)
Case #, Age
hCG (mIU/ml)
hCG-H (mIU/ml)
Case 429, Age 59 Case 34, Age 60 Case 514, Age 61 Case 517, Age 62 Case 543, Age 66 Case 548, Age 68 Case 182, Age 69 Case 18, Age 70 Case 428, Age 54
16.1 32.9 28.5 15.2 17.1 2.5 4.5 31.5 16
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
69 cases, Mean
11.4 6 7.1 Range 2.1 39.0
History
C. Bilateral oophorectomy and primary amennhorea Case 444, Age 34 Case 349, Age 35 Case 519, Age 35 Case 454, Age 36 Case 460, Age 37 Case 322, Age 40 Case 468, Age 29 Case 415, Age 42 Case 319, Age 28 Case 319, Age 28 Case 471, Age 34
3.2 11.5 2.3 3.9 6.9 1.8 6.1 19.4 12.7 33.6 6.4
11 cases. Mean
9.8 6 9.5 Range 1.8 33.6
,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05 ,0.05
Oophorectomy Oophorectomy Oophorectomy Oophorectomy Oophorectomy Oophorectomy Amenorrhea Amenorrhea Oophorectomy Oophorectomy Oophorectomy
There are, however, two other tests that are invaluable. The first test is the FSH test. As shown by Gronowski et al. [17], increased serum FSH of .30 mIU/ml illustrates perimenopause and menopause, or a lack of sufficient steroid feedback to the hypothalamus. An FSH level of .30 mIU/ml means that there is likely to be elevated pituitary hCG present. In the experience of the USA hCG Reference Service, an FSH test ( .30 mIU/ml) correctly predicated pituitary hCG in 29 of 30 cases tested. The second test involves treating patients with a high-estrogen oral contraceptive pill for 3 weeks, which suppresses pituitary hCG and proves whether the hCG is, in fact, from a pituitary origin [15,16,24,28]. These two methods make it easy to prove pituitary hCG is the source of circulating hCG. We emphasize again, however, that production of pituitary hCG in menopause is normal and natural, and it does not mean pregnancy or cancer. Hospitals need to start using the FSH test along with the hCG tests when evaluating women before surgery. If the FSH is .30 mIU/ml, then they need to consider that a positive hCG result is attributable to pituitary hCG. All pregnancies will still be identified by the hCG test.
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References [1] Acevedo HF, Slifkin M, Pouchet GR, Pardo M. Immunochemical localization of a choriogonadotropin-like protein in bacteria isolated from cancer patients. Cancer 1978;41:1217 29. [2] Cohen H, Strampp A. Bacterial synthesis of substances similar to human chorionic gonadotropin. Proc Soc Exp Biol Med 1976;152:408 10. [3] Dominigue G, Johson E. Isolation of subcellular fractions containing immunogenic endobacterial common antigen. Z Immunitatsforsh Exp Klinical Immunol 1974;148:23 8. [4] Backus BT, Affronti LF. Tumor-associated bacteria capable of producing human choriogonadotropin-like substance. Infect Immun 1981;32:1211 15. [5] Maruo T, Segal SJ, Koide SS. Studies on the apparent human chorionic gonadotropinlike factor in crab Ovalipes ocellatus. Endocrinology 1979;104:932 9. [6] Yoshimot Y, Wolfsen AR, Odell WD. Human chorionic gonadotropin-like substance in nonendocrine tissues of normal subjects. Science 1977;197:1977 81. [7] Braunstein GD, Kamdar V, Rasort J, Swaminathan N, Wade ME. Widespread distribution of chorionic gonadotropin-like substance in normal human tissues. Endocrinology 1978;102(Suppl):96. [8] Chen H-C, Hodgen GC, Matsuura S, Lin LJ, Gross E, Reichert LE, et al. Evidence for a gonadotropin from nonpregnant subjects that has physical immunological and biological similarities to human chorionic gonadotropin. Proc Natl Acad Sci USA 1976;73:2885 9. [9] Knight AK, Bingemann T, Cole L, Cunningham-Rundles C. Frequent false positive beta human chorionic gonadotropin in immunoglobulin A deficiency. Clin Exp Immunol 2005;141:333 7. [10] Rotmensch S, Cole LA. False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 2000;355:712 15. [11] Hussa RO, Rinke ML, Schweitzer PG. Discordant human chorionic gonadotropin results: causes and solutions. Obstet Gynecol 1985;65:211 19. [12] Regelson W. Have we found the “definitive cancer biomarker”? The diagnostic and therapeutic implications of human chorionic gonadotropin-beta statement as a key to malignancy. Cancer 1995;76:1299 301. [13] Butler SA, Iles RK. Ectopic human chorionic gonadotropin β secretion by epithelial tumors and human chorionic gonadotropin β-induced apoptosis in Karposi’s sarcoma. Is there a connection? Clin Cancer Res 2003;9:4666 73. [14] Iles RK. Human chorionic gonadotropin and its fragments as markers of prognosis in bladder cancer. Tum Mark Upd 1995;7:161 6. [15] Cole LA, Khanlian SA, Muller CY. Detection of hCG peri- or post-menopause an unnecessary source of alarm. Am J Obstet Gynecol 2008;198:275 9. [16] Cole LA, Sasaki Y, Muller CY. Normal production of hCG in menopause: a medical management dilemma. N Engl J Med 2007;356:1184 6. [17] Gronowski AM, Fantz CR, Parvin CA, Sokoll LJ, Wiley CL, Wener MH, et al. Use of serum FSH to identify perimenopausal women with pituitary hCG. Clin Chem 2008;54:652 6. [18] Cole LA, Ladner DG. Background hCG in non-pregnant individuals: need for more sensitive point-of-care and over-the-counter pregnancy tests. Clin Biochem 2009;42:168 75.
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[19] Cole LA, Laidler L, Muller C. USA hCG Reference Service, 10 year report. Clin Biochem 2010;43:1013 22. [20] Matsuura S, Ohashi M, Chen HC, Shownkeen RC, Hartree AS, Reichert Jr LE, et al. Physicochemical and immunological characterization of an hCG-like substance from human pituitary glands. Nature 1980;286:740 1. [21] Huang SC, Chen HC, Chen RJ, Hsieh CY, Wei PY, Ouyang PC. The secretion of human chorionic gonadotropin-like substance in women employing contraceptive measures. J Clin Endocrinol Metab 1984;58:646 53. [22] Wahlstrom T, Stenman UH, Lundqvist C, Tanner P, Schroder J, Seppala M. The use of monoclonal antibodies against human chorionic gonadotropin for immunoperoxidase. [23] Seki K, Matsui H, Sekiya S. Advances in the clinical laboratory detection of gestational trophoblastic disease. Clin Chim Acta 2004;349:1 13. [24] Cole LA, Khanlian SA. Inappropriate management of women with persistent low hcg results. J Reprod Med 2004;49:423 32. [25] Birken S, Maydelman Y, Gawinowicz MA, Pound A, Liu Y, Hartree AS. Isolation and characterization of human pituitary chorionic gonadotropin. Endocrinology 1996;137:1402 11. [26] Hoermann R, Spoettl G, Moncayo R, Mann K. Evidence for the presence of human chorionic gonadotropin (hCG) and free beta-subunit of hCG in the human pituitary. J Clin Endocrinol Metab 1990;71:179 86. [27] Snyder JA, Haymond S, Parvin CA, Gronowski AM, Grenache DG. Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. Clin Chem 2005;51:1830 5. [28] Cole LA, Khanlian SA, Giddings A, Butler SA, Muller CY, Hammond C, et al. Gestational trophoblastic diseases. 4. Presentation with persistent low positive human chorionic gonadotropin. Gynecol Oncol 2006;102:165 72. [29] Hartree AS, Shownkeen RC, Stevens VC, Matsuura S, Ohashi M, Chen H-C. Studies of human chorionic gonadotropin-like substance of human pituitary glands and its significance. J Clin Endocrinol Metab 1983;96:115 26. [30] Louhimo J, Kokkola A, Alfthan H, Stenman UH, Haglund C. Preoperative hCG β and CA 72-4 are prognostic factors in gastric cancer. Int J Cancer 2004;111:929 33. [31] Carpelan-Holmstrom M, Louhimo J, Stenman UH, Alfthan H, Jarvinen H, Haglund C. Estimating the probability of cancer with several tumor markers in patients with colorectal disease. Oncology 2004;66:296 302. [32] Louhimo J, Alfthan H, Stenman UH, Haglund C. Serum hCG beta and CA 72-4 are stronger prognostic factors than CEA, CA 19-9 and CA 242 in pancreatic cancer. Oncology 2004;66:126 31. [33] Hotakainen K, Haglund C, Paju A, Nordling S, Alfthan H, Rintala E, et al. Chorionic gonadotropin beta-subunit and core fragment in bladder cancer: mRNA and protein expression in urine, serum and tissue. Eur Urol 2002;41:677 85. [34] Hotakainen K, Ljungberg B, Paju A, Rasmuson T, Alfthan H, Stenman UH. The free beta-subunit of human chorionic gonadotropin as a prognostic factor in renal cell carcinoma. Br J Cancer 2002;86:185 9. [35] Odell WD, Griffin J. Pulsatile secretion of human chorionic gonadotropin in normal adults. N Engl J Med 1987;317:1688 91. [36] Odell WD, Griffin J. Pulsatile secretion of chorionic gonadotropin during the normal menstrual cycle. J Clin Endocrinol Metab 1989;69:528 32. [37] Policastro PF, Daniels-McQueen S, Carle G, Boime I. A map of the hCG beta-LH beta gene cluster. J Biol Chem 1986;13:5907 16.
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Human Chorionic Gonadotropin (hCG)
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