Assignment #4: Review of recent paper about Inhibin

Figure 1. Aging and the female reproductive system. Reprinted from Figure 2 in Maturitas 30:193–204 by Soules MR, Battaglia DE, Klein NA; "Inhibin and reproductive aging in women," copyrighted 1998 by Elsevier Ireland Ltd. (22) Redrawn by Kimberly A. Ottinger.

Paper: Overlie, I., Morkrid, L., Anderson, A., Skakkebaek, N., Moen, M., and Holte, A. 2005. Inhibin A and B as markers of menopause: a fiver year prospective longitudinal study of hormonal changes during the menopausal transition. Acta Obstet Scand 2005: 84: 281-285. Available online March 26th 2007.

Summary: Serum Follicle stimulating hormone (FSH) is referred to as the endocrine marker of menopause. This is due to the high levels (5-10 times greater than that of a reproductive follicle age ) of FSH during the postmenopasual period. Menopause is defined after 12 months of amenorrhea following the final menstrual period (FMP). The purpose of this study was to find a more accurate marker of menopause. This was achieved by analysing inhibin A and B, FSH, LH and estradiol among 59 women without hormonal treatment during perimenopause (the period in a womens life in which her body begins its transition into menopause, it includes the years leading up to menopause — anywhere from two to eight years — plus the first year after your final period), and early postmenopause (the time when most of the transitional stress of menopause has passed.)
Random venous blood samples of fifty nine women ranging in age from 46-56 were taken and analyzed annually for five years during the menopausal transition. In the analysis the hormones inhibin A and B, FSH, LH and estradiol were examined. Inhibin, in particularly, was analyzed because it is known as an inhibitor of FSH synthesis and secretion, and therefore could possibly be termed as a direct marker of a decline of ovarian reserve. To relate the hormonal changes to the menstrual cycle, the serum progesterone was analyzed. FSH, LH and estradiol were analyzed by well-characterized immunoassay's and inhibin A and B were determined by specific two site enzyme immunometric assays.

Conclusion: The Results showed a statistically significant increase in serum FSH and LH and a accompanying decrease in estradiol and inhibins during the observation period before the FMP. Inhibin A showed a steady decline from at least four years before the final menstrual period until one year before menopause, whereas inhibin B had a shorter lasting decline from years three to year two before menopause. The continuous decline in inhibin A before the starting decline in inhibin B suggests that an increasing part of the cycle was anovulatory, a menstrual cycle that is characterized by varying degrees of menstrual intervals and the absence of ovulation and a luteal phase. The decrease in inhibin B and the rise in FSH together act as markers of ovarian aging. It was also observed that prior to one year before menopause neither inhibin A nor inhibin B were observed, the absence of these two peptide hormones also act as an indication of the oncoming menopause.

Critique: The paper "Inhibin A and B as markers of menopause" overall was well written and easy to understand. There were some gaps in the paper due to the lack of study in certain areas. For instances there are few reports on the changes in circulating immunoreactive inhibin concentrations measured longitudinally in the same subject during the menopausal transition period. However these discrepancies were taken into consideration. The study also produced results that confirmed and supported previous studies done in this same area, such as the experiment done by Burger et al, who documented a significant decrease in the levels of inhibins A and B before the final menstruating period. Overlie and colleagues also did an excellent job of explaining any possible reasons for the differences in the results such as why inhibin A and B levels were below detection limits in some women. Overall I felt the paper was well written and very easy to comprehend with very little need for further background information.

Future experiment:
Question:What is the relationship between inhibin and pre-puberty (menarche)?
Method: Collect serial samples during a prospective longitudinal trial and measure inhibin levels by a highly specific and sensitive two-site ELISAs.
Results: Inhibin levels will remain restricted before menarche, then rise as puberty proceeds.

Link to paper

Assignment #3 : Function and Pathology

Dimeric Inhibin is produced in the male by the testis (Inhibin B only) and by the ovary in females (both A and B ). Also since inhibins are also produced by placenta and fetal membranes, it has been suggested that there is an involvement in physiological adaptation of pregnancy, at this time inhibin is produced by the fetoplacental unit (Inhibin A only) (McCullagh, R.,2003). All act in direct negative feedback on pituitary production of FSH (Follicle stimulating hormone). Inhibin B expression and secretion are positively correlated with Sertoli cell function, sperm number, and spermatogenic status. The sertoli cells in the testis promote spermatogenesis by increasing the local concentration of testerone, that is stumulated by FSH. Therefore, the sertoli cells produce Inhibin B that acts as a regulatory mechanism with a negative feedback on FSH at the pituitary. (Garem et al., 2002) Women have a different pattern of secretion throughout the menstrual cycle. Inhibin B is produced by the granulosa cells of the developing follicle in regulation that leads to follicular dominance in the menstrual cycle. Inhibin A is also produced by the follicle before ovulation and by the corpus luteum in the luteal phase. (Minami et al., 1995)

Figure 1. (A) Changes of serum inhibin A and inhibin B levels during the menstrual cycle. Redrawn from Groome et al. (1996). (B) Maternal serum inhibin A and pro-C levels during pregnancy and post-partum. According to Fowler et al. (1998).

There are several pathologies of inhibin; impending abortion, hydatidiform mole, and Down's syndrome.

Serum inhibin A measurement is used to predict poor outcome of pregnancy. It acts as a marker of placental dysfunction and damage both in the presence and prior to the onset of the clinical symptoms of recurrent miscarriage. Due to this the inhibin family act as markers of early pregnancy viability. Low levels and a very rapid decline of inhibin A occur in non-viable clinical pregnancies with embryonic failure, therefore patients who have subsequent miscarriage have inhibin A concentrations that are lower than patients who had a live birth (Muttukrishna et al., 2002).

Hydatidiform mole is a disease of the trophoblastic proliferation. This rare mass of growth mimic's pregnancy, it causes human chorionic gondotropin (HCG) levels to increase, therefore, producing a false positive reading on a pregnancy test (Wikipedia, 2007). Inhibin A levels are higher in molar pregnancy without any considerable overlap with normal pregnancy values at the same stage of pregnancy (Florio et al., 2002), this suggests that inhibin A plays a role in measurement in diagnosing molar pregnancies. Also, after molar removal, inhibin A declines considerably to values similar to those measured in non-pregnant women, whereas hCG levels decrease but remain far higher than in non-pregnant women.This suggests that inhibin A is more sensitive than hCG in identifying patients with spontaneous remission after molar evacuation(Florio et al., 2002).

Down's syndrome is a genetic disorder that is caused by the presence of all or part of an extra 21st chromosome (Wikipedia,2007). High maternal serum inhibin A levels are associated with Down's syndrome. Due to this fact, inhibin A levels can be used as part of a multiple prenatal screening marker, because it is not sensitive enough to be used alone (Wenstrom et al., 1999). Also when inhibin subunit is over expressed in second trimester placental tissue of pregnancy this is a indicator of fetal Down's syndrome (Lambert-Messerlian et al., 1998). The conclusion then can be made that increased subunit expression is one of the mechanisms leading to increased levels of inhibin A in serum.

References:

Down syndrome. (2007, March 12). In Wikipedia, The Free Encyclopedia. Retrieved 16:55, March 12, 2007, from http://en.wikipedia.org/w/index.php?title=Down_syndrome&oldid=114544712

Florio P, Severi FM, Cobellis L, Danero S, Bome A, Luisi S and Petraglia F (2002) Serum activin A and inhibin A. New clinical markers for hydatidiform mole. Cancer 94, 2618–2622.[CrossRef][ISI][Medline]

Fowler PA, Evans TW, Groome NP, Templeton A and Knight PG (1998) A longitudinal study of maternal serum inhibin A, inhibin B, activin A, pro-C and follistatin during pregnancy. Hum Reprod 12, 3530–3536.

Garem YF, Arini AF, Beheiry AH, Zeid SA and Comhaire FH (2002) Possible relationship between seminal plasma inhibin B and spermatogenesis in patients with azoospermia. J Androl 23, 825–829.

Hydatidiform mole. (2007, February 19). In Wikipedia, The Free Encyclopedia. Retrieved 14:43, March 12, 2007, from http://en.wikipedia.org/w/index.php?title=Hydatidiform_mole&oldid=109414694

Lambert-Messerlian GM, Luisi S, Florio P, Mazza V, Canick JA and Petraglia F (1998) Second trimester levels of maternal serum total activin A and placental inhibin/activin and ßA subunit messenger ribonucleic acids in Down syndrome pregnancy. Eur J Endocrinol 138, 425–429.[Abstract]

McCullagh, R. (2003). Inhibin. Inhibin Fertility and Reproduction Function. Retrieved March 12, 2007 from http://www.inhibin.com/Home/Static.aspx?PageID=0

Minami S, Yamoto M and Nakano R (1995) Sources of inhibin in early pregnancy. Early Pregn 1, 62–66.

Muttukrishna S, Jauniaux E, Greenwold N, McGarrigle H, Jivraj S, Carter S, Elgaddal S, Groome N and Regan L (2002) Circulating levels of inhibin A, activin A and follistatin in missed and recurrent miscarriages. Hum Reprod 17, 3072–3078.

Wenstrom KD, Owen J, Chu DC and Boots L (1999) Prospetic evaluation of free ß-subunit of human chorionic gonadotropin and dimeric inhibin A for aneuploidy detection. Am J Obstet Gynecol 181, 887–892.[CrossRef][ISI][Medline]

Second Assignment

My Favorite Hormone Structure

Figure 1: Multiple amino acid Sequence Alignment of Inhibin in Rainbow trout (BAB19272), Zebra fish (NP 571143), Rhesus monkey(NP 001028127), Norway rat(NP 036722), and house mouse(NP 034694) . Alignments were made using ClustalW software. Legend : ":" conserved substitutions , "*" residues are identical in all sequences of the allignment, "." semi-conserved substitutions.

Inhibin is a heterodimeric glycoprotein that is found in the seminal plasma and follicular fluid. It is secreted from the granulosa cells of the ovary in females, and from the Sertoli cells of the testes in males, to control secretion of Follicle Stimulating Hormone. Inhibin is produced in the placenta, gonads, pituitary gland and other organs (Wikipedia, 2007). The secondary structure of inhibin consists of one alpha chain that is ~18 kDa and one beta chain that is ~14kDa, these two subunits are linked by disulfide bridges. Each subunit ( alpha and beta) is produced from a seperate gene and is produced as a large precurser protein. There are two separate beta-subunit genes, and thus two distinct proteins (beta-A subunit and the beta-B subunit). Therefore there are two "kinds" of inhibin, inhibin-A or inhibin-B, and each may exist in 7 to 9 different molecular forms. Due to the many combinations there are a number of different dimeric inhibin forms(Hopko JL et al.,1994). Inhibin in its "mature" form has a molecular weight of 32,000 daltons (Ying, 1988).
Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) contain identical alpha subunits of 92 amino acids, however there beta chains vary, FSH has 118 and LH has 121 amino acids. All three hormones (FSH, LH and Inhibin) are involved in ovulation.
The known receptors of Inhibin are poorly understood when compared to its structurally similiar molecule activin. Inhibin is known as an activin antagonist and operates by competing for activin receptors rather then having its own receptors. However , inhibin is also known to bind with great affinity and specificity with membrane-binding proteins that could possibly be the supposed inhibin receptor. (Robertson et al.,2000)




References

Hopko Ireland JL, Good TE, Knight PG & Ireland JJ 1994 Alterations in amounts of different forms of inhibin during follicular atresia. Biology of Reproduction 50 1265-1276.

Inhibin. (2007, February 22). In Wikipedia, The Free Encyclopedia. Retrieved 17:29, February 25, 2007, from http://en.wikipedia.org/w/index.php?title=Inhibin&oldid=109986814
Robertson, DM., Herton R. & Farnworth PG. (2000). Is the action of inhibin mediated via a unique receptor? Reproduction. The Journal of the Society for Reproduction and Fertility. 5, 131-135. Society of Reproduction and Fertility. Retrieved February 25th 2007 from http://ror.reproduction-online.org/cgi/content/abstract/5/3/131

Ying, SY. (1988). Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocrine Reviews 9 267-293. Retrieved February 25th 2007 from www.medvet.umontreal.ca/crra_ang/CAP_inhibine.pdf

My Favorite Hormone: Inhibin

Inhibin is a peptide hormone that inhibits FSH (Follicle Stimulating Hormone) synthesis and secretion, and contributes to regulation of the menstrual cycle (Wikipedia, 2007).
It is made up of alpha and beta subunits that are linked by disulfide bonds. The alpha subunits remain identical while the beta subunits differ (A or B), creating two forms (McCullagh, R., 2003). Therefore, inhibin belongs to the transforming growth factor - B (TGF-B) family (J Clin, 2005).
In females, FSH stimulates the secretion of inhibin (A and B) from the granulosa cells of the ovary, and inhibin in turn, suppresses FSH (Kipp et al., 2007). These peptides are diminished by GnRH and enhanced by insulin like growth factor - 1 (IGF-1) (Wikipedia, 2007). Both forms (A and B) peak at different times during the menstrual cycle. Inhibin B peaks between early and mid follicular phase and then peaks for the second time during ovulation. Inhibin A peaks during mid-luteal phase (Wikipedia, 2007).
In men, inhibin is found only in its B form. It inhibits FSH production as in the females, and is produced by the testes (McCullagh, R., 2003).
These peptides are also commonly used for prenatal testing. The prenatal quad screen is typically administered at a gestational age of 16-18 weeks. If results show elevated inhibin A ( with increased beta-hCG, and decreased AFP and estriol) a fetus with down syndrome is assumed ( New England Journal of Medicine, 2006).


References:

Inhibin. (2006, December 7). In Wikipedia, The Free Encyclopedia. Retrieved 15:47, January 30, 2007, from http://en.wikipedia.org/w/index.php?title=Inhibin&oldid=92601534

J Clin Endocrinol Metab. 2005 Jan; 90(1); 271-8. Epub 2004 Oct 13.

Kipp et al., Endocrinology, 2007 Jan 25, [Epub ahead of print] "Neonatal Exposure to Estrogens Suppresses Activin Expression and Signaling in the Mouse Ovary."

"Dimerk Inhibin A as a marker for Down's Syndrome in Early Pregnancy". New England Journal of Medicine, The 334(19); 1231-1236. Retrieved 2006-08-04.

McCullagh, R. (2003). Inhibin. Inhibin Fertility and Reproduction Function. Retrieved January 29th 2007 from http://www.inhibin.com/Home/Static.aspx?PageID=0