Corpus Luteum

The corpus luteum is a remarkable, transiently functioning organ that provides the endocrine conditions that are necessary and sufficient for the establishment and maintenance of early pregnancy. On a weight basis, it is the most productive steroid-secreting tissue in the body. It is abruptly formed from the remnants of the preovulatory follicle, and it undergoes continuous change thereafter. This chapter presents the corpus luteum in the context of its changing properties over time in the early, middle, and late luteal phase in cycles without conception and during early and late pregnancy. Themes for understanding the corpus luteum center on the sudden induction of an immense steroidogenic capacity, the importance of new vessel formation to this process, and the supervening effects of apoptosis in the event of conception failure.

The corpus luteum is formed by the action of luteinizing hormone (LH) on the mature preovulatory follicle. Ensuing events, including steroidogenic outpouring, programmed senescence, and capacity for extension by gestation, depend on features characteristic of an adequately developed preovulatory follicle, including, most importantly, the number and LH receptivity of the granulosa cell population, both of which are follicle-stimulating hormone (FSH)–dependent properties. Acquisition of LH receptor (LHR) by preovulatory granulosa cells results from estrogen-stimulated and FSH-stimulated transcription of the LHR gene, the actions of which are mediated largely by intracellullar cyclic adenosine monophosphate (cAMP).^1,2 Actions of LH and human chorionic gonadotropin (hCG) define the functional unfolding of luteal events and are thought to be exclusively dependent on activation of this single, G-protein–coupled receptor. LHR-mediated effects occur primarily via the Gs/adenylyl cyclase/cAMP/PKA signaling pathway, although evidence for activation of other signaling pathways (e.g., inositol phosphate pathway) and possible roles for these is accumulating.³ The luteotropic action of LH or hCG on follicles that are not mature can produce luteinization of the theca, where LHRs are present, but does not set in motion the distinctive sequence of changes in morphology and function of the granulosa and theca that characterize the corpus luteum.

In ovulatory cycles, there is an increase in progesterone levels that begins before the LH surge, thought possibly to contribute to the positive feedback signal for pituitary release of LH (Fig. 1).^4,5,6,7 This harbinger of luteal function is accompanied by a preovulatory increase in circulating 17-hydroxyprogesterone, the levels over time of which differ in pattern from those of progesterone by decreasing after the LH peak, in contrast to the rapid postovulatory increase in progesterone levels.^5,8 These events may reveal an innate tendency for the granulosa cells of the mature follicle to secrete progestins, as occurs spontaneously when such cells are studied in vitro without an LH signal.⁹ They foretell the remarkable increase in the overall rate of steroidogenesis that soon will be under way: In a few days, the steroidogenic output of the ovary increases from a few hundred micrograms of estrogen to 20 mg or more of progesterone daily—a 100-fold increase. Ovulation marks a shift in inhibin production from the inhibin B dominance of the follicular phase to predominant production of inhibin A, the levels of which roughly parallel steroid secretion by the corpus luteum. Late follicular phase granulosa cells elaborate alpha subunit and beta (B) subunit mRNA in response to FSH and LH.¹⁰

The increase in steroidogenesis in the periovulatory period is accompanied by granulosa cell proliferation and considerable functional and structural reorganization that eventuate in the distinct morphology of the corpus luteum. Expression of the transcription factor early growth response factor-1, known as a coordinator for multiple transcriptional alterations in circumstances of tissue change, is induced in human granulosa cells by hCG. Expression of this growth factor also is stimulated by cholinergic activation of muscarinic receptors on granulosa cells.¹¹ Activation of muscarinic receptors also blocks gap junctions via phosphorylation of connexins therein and stimulates cell proliferation via increases in intracellular calcium, together suggesting that cholinergic mechanisms may participate in the rapid reprogramming of granulosa cells in the periovulatory period.¹²

Histology and Ultrastructure of the Early Corpus Luteum

During the first several days after ovulation, there are important changes in histoanatomy, histology, and ultrastructure that describe the transformation of the mature follicle into the corpus luteum.^4,13,14,15 At first, there is little to distinguish the histology of the corpus luteum from that of the late preovulatory follicle.^4,14 The granulosa cells are not yet luteinized, or lipid-laden, and this layer remains avascular. Theca cells remain large and lipid-laden, and vessels of the theca are engorged. There may be a small amount of bleeding into the central cavity and, in early specimens, this feature may be the chief clue that ovulation has occurred.

Mitoses in the granulosa layer are seen in this early phase, and luteinization of granulosa cells (enlargement and accumulation of intracellular lipid) begins in earnest. Ultrastructurally, this change in granulosa lutein cells is accompanied by an accumulation of cytoplasmic lipid droplets, the appearance of a well-developed granular endoplasmic reticulum, and tubular cristae in the mitochondria—all changes typical of actively steroidogenic cells. There is organization of the cell into a peripheral zone of tubular endoplasmic reticulum, with few lipid droplets and mitochondria, and a central zone of mitochondria and well-dispersed Golgi, often with intervening parallel arrays of rough endoplasmic reticulum.^13,15,16,17 This geographic arrangement may allow for accession and presentation of cholesterol from the lateral cell border to the mitochondria and for steroid to be passed to the Golgi.^16,17

The transformation of the follicular granulosa cells to the granulosa-lutein cell mass of the corpus luteum is accompanied by the formation of new vessels that develop rapidly over the next few days. The formation of new vessels supports luteal function and export of luteal products and is mediated by vascular endothelial growth factor (VEGF), acting in a paracrine fashion.^18,19,20 Locally elaborated VEGF drives endothelial cell proliferation, and endothelial cells comprise more than 50% of the cell population of the corpus luteum.^21,22 Cell proliferation in the corpus luteum is limited almost exclusively to vascular endothelial cells (85% of mitotically active cells are endothelial cells) and is greatest in the young corpus luteum (Fig. 2).^21,23,24

Steroid Secretion by the Early Corpus Luteum

Development of the extraordinary steroidogenic productivity of the corpus luteum is realized within a few days of ovulation. Acquisition of substrate is accomplished by low-density lipoprotein (LDL) receptor–mediated binding and internalization of very-low-density lipoprotein–associated cholesterol.^25,26,27,28 Cholesterol molecules thus acquired next must reach the inner mitochondrial membrane, a step mediated by the sterol transfer protein StAR (steroidogenic acute regulatory protein).^29,30,31 Finally, at the inner mitochondrial membrane, cytochrome P-450 side-chain cleavage (P-450scc) enzyme effects the synthesis of pregnenolone from cholesterol. LH acts via the cAMP second messenger system, in synergy with insulin, to enable each of these three key steps: increased expression of LDL receptors, expression of StAR protein, and of P-450scc enzyme.^32,33 Expression of StAR is mediated by the transcription factors steroidogenic factor 1, CCAAT/enhancer binding protein beta, and other as yet uncharacterized transcription factors and coregulators.³¹ StAR mRNA expression is greatest in the newly formed corpus luteum (Fig. 3).³⁴ Pregnenolone, the immediate product of side-chain cleavage of cholesterol, is transformed into progesterone by the enzyme 3β-hydroxysteroid dehydrogenase, Δ 4-5-isomerase located in smooth endoplasmic reticulum. The transport of newly formed progesterone from the cell is thought to be a process of passive diffusion³⁵; however, an active secretory mechanism for steroidogenic cells has been proposed.^36,37

Progesterone concentrations are 10-fold higher in the peritoneal fluid than in peripheral blood in the days immediately after ovulation, probably as a result of impeded vascular export from the corpus luteum.³⁸ The rate of secretion through the peritoneal compartment may be substantial because there is ample vascularized surface area for absorption, but progesterone entering this compartment is largely metabolized before reaching the peripheral circulation because of the hepatic first-pass effect of the splanchnic circulation.³⁹ Peritoneal fluid levels of progesterone decrease as the luteal phase advances, presumably as more steroid finds its way into the circulation directly through newly forming vascular channels in the corpus luteum. This interpretation is supported by the finding that the maximum tissue levels of progesterone are found in the early corpus luteum and decline thereafter.⁴⁰

The pattern of progesterone secretion into the bloodstream by the early corpus luteum is dominated by a basal or tonic secretion, with little in the way of a pulsatile response to the episodic secretion of LH by the pituitary (Fig. 4).⁴¹ Progesterone secretion of the early corpus luteum is augmented little by hCG administration.^42,43,44 This picture correlates with the functional predominance of the larger of the two functional and morphologic cell types identified in vitro in preparations of dispersed luteal cells.

Isolated luteal cells studied in vitro can be grouped into two populations, determined by size, that exhibit different secretory physiology.^44,45,46,47 The large cells possess a higher basal rate of progesterone secretion than the small cells, but they are indifferent to hCG stimulation, are devoid of LHRs, and show enhanced estrogen biosynthesis when stimulated by FSH. By contrast, hCG markedly increases progesterone synthesis by small luteal cells, which do have LHRs, but in which estrogen secretion is not enhanced by FSH. These two cell types exhibit functional parallels with the theca and granulosa cells of the preovulatory follicle and may correspond to the granulosa-derived and theca-derived components of the corpus luteum.^16,44,45

In vivo, the overall function of the corpus luteum is LH dependent, as shown by prompt luteolysis after administration of antisera to LH⁴⁷ or gonadotropin-releasing hormone (GnRH) antagonists or agonists^48,49,50,51 or after withdrawal of pulsatile GnRH in GnRH-dependent individuals.^52,53 Clinically, when ovulation is induced with pulsatile GnRH for hypothalamic amenorrhea, maintenance of luteal function requires continued, pulsed GnRH administration or administration of hCG.^54,55

Peptide Secretion by the Early Corpus Luteum

Inhibin has been identified as a secretory product of luteal cells in vitro.^56,57 Levels of inhibin A begin to rise in the late follicular phase, peak in the mid luteal phase, and decline with luteal demise. Inhibin B exhibits high levels in the circulation in the late follicular phase and early luteal phase, and these decrease thereafter. Circulating levels of inhibin during the luteal phase are accounted for by the corpus luteum⁵⁸ and roughly parallel progesterone levels.⁵⁹ Granulosa luteal cells express mRNA for the inhibin alpha subunit to a greater extent than the mRNAs for beta A and beta B subunits, which is consistent with luteal production of inhibin A, inhibin B, and free inhibin alpha subunit.^60,61 The LH-hCG dependence of luteal inhibin secretion has been confirmed in vitro⁵⁶ and in vivo.⁴⁹ The luteal phase depression of FSH levels may reflect in part the FSH-lowering effect of inhibin.⁶² This function would serve to avert the chaotic consequences of the superimposition of active folliculogenesis on luteal function.⁶³ In addition to modulation of gonadotropin secretion, inhibin may exert paracrine influences on luteal function and development.

Abnormalities of the Early Corpus Luteum

The postovulatory rise in progesterone levels is delayed in some women, constituting a specific defect in the onset of luteinization. This special form of luteal dysfunction has been associated with a lag in the progression of secretory change in the endometrium and infertility.^64,65,66

Hemorrhage into the central cavity of the corpus luteum is seen normally, but occasionally it can be excessive and warrant surgical attention because of pain or hemoperitoneum. Such clinical events can occur at any time during the life span of the corpus luteum of the cycle and during early pregnancy. Anticoagulant therapy is the sole known antecedent for these rare, otherwise sporadic events.⁶⁷

By the mid luteal phase, the blood levels of progesterone, estradiol, and inhibin have reached their maxima, and 17-hydroxyprogesterone levels achieve a second peak.⁸ Now, at the full expression of its secretory capacity, the corpus luteum is poised at the junction of a course leading to regression and demise, in the nonpregnant cycle, or rescue and extended function, should pregnancy occur.

Histology and Ultrastructure of the Corpus Luteum of the Mid Luteal Phase

Histologically the granulosa layer is fully luteinized, festooning the margin of organelle (Fig. 5). Central hemorrhage becomes isolated from the underlying granulosa by an organizing layer of fibroblasts. Fresh bleeding into the central cavity still is seen commonly in surgical specimens. Theca cells have regressed except in regions where they have invested infolding septae, the theca lutein cells.^13,14,68 Small darker cells, the so-called K cells, correlate ultrastructurally with perivascular macrophages.¹⁶ Distinctive ultrastructural features of active granulosa lutein cells now include extensive development of granular endoplasmic reticulum,⁶⁹ microfilaments investing the cytoplasmic periphery bordering intercellular and intracellular canaliculi,¹⁷ and patches of microvilli that protrude into the perivascular space.¹⁶ These modifications suggest enhanced absorptive capacity, probably for cholesterol. Areas of granular endoplasmic reticulum also are seen and may reflect synthesis of peptides such as relaxin and inhibin (Fig. 6).¹⁶

Steroid Secretion by the Corpus Luteum of the Mid Luteal Phase

The progesterone secretory response of the corpus luteum to exogenous hCG is maximal at this luteal stage.^42,43,44 Correspondingly the LH pulse–dependent transient increases in progesterone levels become more pronounced, and basal secretion is proportionately less important (see Fig. 4).⁴¹ This evolution in secretory response to LH and hCG may reflect an increasing functional predominance of the smaller luteal cell type seen in vitro⁷⁰ and foretells the hCG responsiveness that will be required of the corpus luteum in the event of conception and implantation. StAR mRNA transcripts are diminished only slightly relative to the high levels of the early corpus luteum, whereas StAR protein abundance remains at least as great (see Fig. 3).³⁴ Secretory bursts of progesterone occur with decreasing frequency, reflecting the decreased LH pulse frequency resulting from the effect of progesterone on the hypothalamic GnRH pulse generator (see Fig. 4).⁷¹ Expression of the function of the mature corpus luteum depends on the vascular investment of the organelle. Luteal function at this stage is compromised if VEGF-mediated angiogenesis is impaired.⁷² Expression of VEGF and its receptor, flt-1, remain as high as in the early luteal phase.²⁰

Peptide Secretion by the Corpus Luteum of the Mid Luteal Phase

Inhibin B levels have started a decline by the midluteal phase, whereas inhibin A levels reach their maximum. In vitro inhibin production by dispersed luteal cells is stimulated by hCG, but not FSH, and more so in the early and mid luteal phase than in late luteal phase tissue.⁷³ Inhibin A infused during the mid luteal phase reduces levels of FSH, without altering LH or progesterone levels or altering luteal phase length.⁶²

Hypothalamic-Pituitary-Luteal Regulation

The regulatory relationship of corpus luteum function to the trophic influence of LH is poorly understood. The corpus luteum remains dependent on LH (or hCG) throughout its life span, and progesterone in turn modulates gonadotropin secretion, most notably by effecting a decrease in the frequency of gonadotropin pulses as the luteal phase evolves.⁷¹ This effect can be attributed to progesterone-mediated increase in opioid levels affecting the medial basal hypothalamus and the GnRH pulse generator.^74,75 Progesterone and inhibin also may affect the secretion of gonadotropins directly at the level of the pituitary. In contrast to the relation of most endocrine glands to their trophic support, however, there is little evidence of an active feedback loop for luteal secretion and secretion of gonadotropins. In short-term experiments, exogenous augmentation of progesterone levels does attenuate LH secretion.⁷⁵ Luteal phase progesterone levels in spontaneous cycles correlate only weakly, however, if at all, with mean LH levels.^76,77 In particular, there is no evidence for a compensatory increase in LH secretion when progesterone levels are low in defective luteal phases⁷⁷ or after luteectomy.⁷⁸

Functional Abnormalities of the Corpus Luteum of the Mid Luteal Phase

The lower limits of normal for progesterone levels during the mid luteal phase are not well defined. Progesterone levels are frequently normal when measured during defective luteal phases, defined in terms of delayed secretory transformation of the endometrium. When carefully studied, integration of progesterone levels does correlate with clinically defined luteal adequacy, although a troubling overlap of normal and abnormals persists.⁷⁷ Mid luteal inhibin A levels are decreased in women with luteal phase deficiency, defined by diminished mid luteal progesterone levels.⁷⁹ Mid luteal inhibin A and immunoreactive inhibin alpha subunit are not diminished among women with luteal deficiency defined by endometrial maturation who have normal mid luteal progesterone levels.^80,81 The poor correlation of peripheral progesterone levels with other determinants of luteal function may rest in the unreliability of single samples in representing the episodically variable levels of the hormone and the problem of accounting for its extensive, perhaps variable plasma binding to cortisol binding globulin and albumin.⁶⁵

By the 10th to 11th postovulatory day, progesterone secretion declines despite continued LH support. Now, LH pulses occur at lower frequencies than previously, and functional luteolysis has started. Functional luteolysis can be defined as the progressive decline in the capacity of the corpus luteum to respond to LH and hCG. Without rescue by hCG, progesterone secretion now becomes negligible over the next 2 to 3 days. This process can be overcome only by the timely and rapid increase in trophic support generated by an hCG from a successfully established gestation. Luteolysis is an essential conclusion to the nonconception cycle: It permits re-establishment of conditions supporting renewed folliculogenesis and endometrial regeneration.

Histology and Ultrastructure of the Regressing Corpus Luteum

Histologic evidence of regression includes shrinkage of cells in the granulosa layer. Theca and granulosa cells are progressively vacuolized, accounting in the former for the distinctive appearance of so-called mulberry cells.¹⁴ Histochemical studies show rapid loss of key steroidogenic enzymes.⁸² Ultrastructurally, there is breakdown of the organization of the endoplasmic reticulum, Golgi regression, and appearance of lipid droplet inclusions.^13,69 The lutein zone exhibits progressive fibrosis, which presages ultimate hyalinization. Connective tissue organization of the central cavity continues, but even in the latest specimens fresh hemorrhage often is encountered.

Steroid Secretion by the Regressing Corpus Luteum

Progesterone secretion by the regressing corpus luteum increasingly is accounted for by episodic bursts in response to LH pulses.⁴¹ LH pulse frequency is at its lowest ebb; sometimes only a handful of pulses are seen in 24 hours. Progesterone peak amplitudes decline, and because basal secretion is now negligible, progesterone levels fall to preovulatory values in the long pulsatile intervals (see Fig. 4).⁴¹

Peptide Secretion by the Regressing Corpus Luteum

Inhibin secretion declines in a pattern parallel to that of progesterone.^59,83,84 Declining steroid and peptide levels lead to increased GnRH pulse frequency and increased secretion of FSH, allowing initiation of the following cycle. Release from the inhibition of inhibin A does not seem to be as important as the effect of decreasing levels of estradiol in allowing re-emergence of FSH secretion during the transition to the follicular phase.⁸⁵ Estradiol suppresses the increased inhibin B levels observed after menses, and the increase in levels of inhibin B and estradiol at the initiation of the next cycle depends on the increased gonadotropin pulse frequency that occurs after menses.⁸⁶

Mechanism of Luteolysis and Apoptosis

Part of the decline in luteal function may be accounted for by the increasingly desultory secretion of LH in the late luteal phase,⁸⁷ but experimentally induced decreases in LH pulse frequency⁸⁸ or amplitude⁸⁹ alone do not cause luteal failure. The progressive refractoriness of the corpus luteum to LH stimulation is the essential expression of luteolysis. When the cycle has ended, little if any progesterone secretion can be evoked from the regressed corpus luteum, even by large doses of hCG.^42,70,90

Refractoriness to LH stimulation in vivo is reflected in in vitro studies. A decline in available LHR sites accompanies luteolysis,^91,92,93 but it is not clear whether this is a causal or a secondary event.⁹⁴ The declining secretory response to LH and hCG is accompanied by a decreasing secretory response to cAMP and its analogues, evidencing a role for postreceptor changes in functional luteolysis. Reduced transcription of StAR protein mRNA and dwindling expression of StAR protein occur and are likely an important component of the functional decline of the late corpus luteum (see Fig. 3).^34,95

Prostaglandin F_2α (PGF_2α) is well established as the luteolysin in some species where it originates in the endometrium and traverses the utero-ovarian vasculature to reach the corpus luteum.^46,96,97,98 PGF_2α abrogates LH stimulation of cAMP production in vitro,^99,100 possibly by decreasing LHR numbers^101,102,103 or by actions downstream in the receptor/second messenger cascade.¹⁰⁴ PGF_2α suppresses basal and gonadotropin-stimulated StAR levels and stimulates expression of DAX-1, a negative transcription factor that reduces StAR promoter responsiveness to cAMP.¹⁰⁵ A luteolytic effect of PGF_2α acting to decrease perfusion of the corpus luteum also has been proposed, and vascular regression is observed in the aging corpus luteum.^22,24,106 The stimuli for angiogenesis fade; mRNA and protein expression for VEGF and its receptor, flt-1, are diminished in the corpus luteum of the late luteal phase.²⁰ PGF_2α originating from the nonpregnant secretory endometrium is not the luteolysin in the primate, in which a normal luteal span is seen in hysterectomized primates.^107,108,109 Data from humans and nonhuman primates support a luteolytic role for intraluteally generated PGF_2α,^{40,99,110,114} and luteolysis can be evoked in nonhuman primates by intraluteal infusion of PGF_2α¹¹⁵ Peripheral infusion of PGF_2α does not cause luteolysis,^116,117 however, perhaps because these compounds are metabolized rapidly in the pulmonary circulation. Prostaglandin synthesis inhibitors do not override luteolysis^118,119 or extend the luteal phase, an observation explained by the known luteotropic influence of prostaglandins (e.g., prostaglandin E) other than PGF_2α.^120,121

Estrogen has a luteolytic effect, in vivo and in vitro,^{103,122,123,124,125} and the estrogen content of regressing corpora lutea is higher than at earlier stages.¹²⁶ The direct luteolytic action of estrogen seen in in vitro observations may result from estrogen-induced increases of PGF_2a production by luteal cells.^115,127In vivo effects of estrogen on luteal function also may include estrogen inhibition of LH secretion. High luteal-phase estrogen levels may account for luteal defects in some instances of induced ovulation^54,128 and ovarian hyperstimulation.¹²⁹

Regression of the corpus luteum is accompanied by programmed cell death, or apoptosis.¹³⁰ This universal metazoan mechanism for eliminating unneeded cells depends on the release and activation of specific, mitochondrially sequestered enzymes that include apoptosis-inducing factor and serine proteases known as caspases.¹³¹ Caspase activation by proapoptotic proteins such as Bax and inhibition by antiapoptotic signals such as Bcl-2 parallel observed apoptosis. Bcl-2 expression and mRNA are high in the mid luteal phase and diminished in the regressing corpus luteum, whereas Bax is most prevalent in the regressing corpus luteum.¹³²

Functional Abnormalities During Luteal Regression

Luteal function can be abnormally short in duration, reflecting premature or accelerated luteolysis, and this can lead to infertility and perhaps recurrent pregnancy loss.¹³³ Lower progesterone levels described throughout the luteal phase in short luteal-phase cycles suggest a global deficiency of luteal physiology, rather than a simple truncation of normal events.^134,135 Several studies implicated abnormalities of gonadotropin secretion during preceding follicular phase in the genesis of the shortened luteal phase.^{77,134,135,136,137,138,139}

Abnormal extension of luteal function also has been described. Termed Halban’s syndrome, the clinical picture is one of recurrent, functioning cystic corpora lutea, with abnormal vaginal bleeding. It is possible that clinical events attributed to this diagnosis occurred because of early, failing intrauterine or clinically occult tubal pregnancies. Recurrent, nongestational extension of luteal function has been documented rarely since the advent of sensitive blood and urinary hCG assays.¹⁴⁰

In the event of conception and implantation, rising levels of hCG originating from the trophoblast transform the corpus luteum histologically and morphologically. There are quantitative and qualitative changes in secretory activity, which include increased and smoothed secretion of progesterone (owing to the nonsaltatory nature of hCG levels), increasing secretion of inhibin, and the onset of secretion of relaxin. A new wave of vascular endothelial proliferation in the corpus luteum occurs in response to the rising hCG of early pregnancy.^22,24

Histology and Ultrastructure During Early Pregnancy

The corpus luteum generally is enlarged, principally by virtue of an increased volume of the central cavity.¹⁴¹ Connective tissue surrounding the corpus luteum becomes hyperplastic and extensively vascularized. The theca luteum layer becomes prominent, and this zone appears to be the site of early cellular response to hCG.¹⁴² Ultrastructurally, functional cells resemble those of the midluteal phase, but with an accentuation of the compartmentalization of organelles.¹³ Apoptosis, characteristic of the regressing corpus luteum of the nonpregnant cycle, is virtually inapparent in the corpus luteum of early pregnancy. The absence of apoptosis is paralleled by sustained levels of Bcl-2, characteristic of the midluteal corpus luteum, and absence of the expression of Bax, which is seen in the regressing corpus luteum.¹³³ These alterations may reflect the influence of hCG, which increases the mRNA and protein levels of Bcl-2 and decreases those of Bax when midluteal cells are incubated in vitro (Fig. 7).¹³³

Steroid Secretion by the Corpus Luteum of Early Pregnancy

In early pregnancy, progesterone secretion and that of estradiol and 17-hydroxyprogesterone slightly exceed that of the nonpregnant mid luteal phase.^{143,144,145,146} The mechanism of the hCG-induced abrogation of luteolysis is incompletely understood but may include modulation of intraluteal prostaglandin synthesis.^147,148 The enhancement of progesterone secretion by rising hCG is seen from near the time of implantation onward,¹⁴⁵ but progesterone secretion seems to increase slowly, if at all, thereafter. The gradual increase in levels of progesterone in early pregnancy is accounted for more readily by increasing progesterone secretion by the trophoblast.¹⁴⁹ The corpus luteum can be estimated to account for approximately 76% of the circulating progesterone at 6 weeks, 50% by 10 to 11 weeks, and 33% by 14 to 15 weeks.¹⁵⁰ The decreasing contribution of the corpus luteum to circulating progesterone also is reflected by the decline in blood levels of 17-hydroxyprogesterone, exclusively a luteal product, relative to the gradually rising progesterone levels of early pregnancy.^144,151 The studies of Csapo and colleagues definitively delineated the indispensability of the corpus luteum to early pregnancy maintenance until about the seventh week¹⁵² and determined that this essential role could be accounted for entirely by progesterone.^149,153,154 The evolution of gestational dependency on the corpus luteum to independence was called the luteoplacental shift and seems to correspond to the ability of the trophoblast to maintain progesterone levels at levels exceeding approximately 5 ng/mL.

The modestly enhanced, but relatively constant, luteal output of progesterone in early pregnancy is accounted for by hCG. The dramatic rate of rise of hCG levels seen in early gestation seems essential to the maintenance of progesterone secretion.^150,155 Progressive refractoriness to hCG at fixed doses is found in vivo^156,157 and in vitro.⁷⁰ By contrast, administration of hCG in increasing doses—in a manner mimicking early pregnancy—results in extension of luteal function (Fig. 8).^42,158

Failure of decreasing or inadequately increasing hCG levels to sustain luteal progesterone production in early pregnancy can be attributed to desensitization of the granulosa cells. Desensitization of LHR function has been shown in vitro to include (1) internalization of receptor down-regulation and (2) uncoupling of the receptor from functional interaction with its associated G-protein. Both features of this post-transcriptional modulation of receptor have been shown to occur as a result of receptor phosphorylation (an accompaniment of G-protein activation) and subsequently are mediated by beta-arrestin proteins that bind the phosphorylated receptor.^3,159 This process may explain how the smoothly increasing levels of hCG as opposed to episodic levels of LH may facilitate the striking and progressive refractoriness of the corpus luteum of early pregnancy to hCG support. Clinically, this phenomenon is reflected by the low progesterone levels seen when hCG levels fail to increase normally in early pregnancy. When pregnancies with abnormally rising hCG are intrauterine, resulting progesterone secretion is low, effecting inadequate decidual support and spontaneous abortion. Because low progesterone levels on a single determination are a marker for poor hCG rise, spot progesterone levels have utility as a screen for ectopic pregnancy.¹⁶⁰

The progressive refractoriness of the corpus luteum to LH and hCG that constitutes functional luteolysis seems to extend into pregnancy and is overcome only by the rapid rate of rise of hCG. This refractoriness may be a result of a decrease in LH-hCG receptor number or affinity¹⁶¹; increased hCG receptor occupancy has been documented in early pregnancy.⁹² Levels of hCG do not vary, as do those of LH with its episodic secretion and shorter half-life; this is a likely explanation for the fact that the short-term variation in levels of progesterone characteristic of the late luteal phase is reduced in early pregnancy. Substantial short-term variability in progesterone levels remains, however, and may be accounted for by short-term variation in volume of distribution and metabolism of the hormone (Fig. 9).¹⁶²

Peptide Secretion by the Corpus Luteum of Early Pregnancy

Relaxin, a polypeptide with homologies with insulin and nerve growth factor, is produced by the corpus luteum of early pregnancy. It circulates in small quantities in the final days of the nonpregnant cycle,¹⁶³ but this increase is accelerated and continued in cycles of conception under the influence of hCG, independent of hCG stimulation of progesterone secretion.^164,165,166 It can be evoked by the administration of hCG late in the luteal phase of a nonpregnant cycle,¹⁶⁷ and levels in multiple pregnancy are related to the number of concepti.¹⁶⁸ In early pregnancy, corpus luteum volume correlates more closely with hCG and relaxin levels than levels of progesterone, and relaxin levels correlate with levels of hCG.¹⁶⁹ Relaxin increases expression of VEGF by endometrial cells in vitro and may play a role in endometrial neovascularization.¹⁷⁰ In many species, relaxin induces remodeling of connective tissue of the birth canal and inhibits myometrial contractility.¹⁷¹ Known nonreproductive effects of relaxin, of unclear significance to the physiology of human pregnancy, include cardiovascular, breast, antiplatelet, and pituitrophic activities.¹⁷² Placenta and decidua are sites of synthesis of relaxin as well, which may explain higher levels of relaxin observed in pregnancies in diabetic women.^173,174 Aluteal pregnancies achieved through assisted reproduction techniques are relaxin deficient, without apparent consequences to implantation, pregnancy maintenance, or mechanism of labor and delivery.^{166,175,176,177} Without an essential function in human pregnancy, the time-dependent and signal-dependent luteal secretion of relaxin points to ongoing differentiation of function within components of the corpus luteum long after it is formed.

Expression of inhibin alpha subunit and beta A subunit continues in the corpus luteum of early pregnancy.⁶¹ Also there is evidence that under the influence of hCG, the corpus luteum is the source of the increase in circulating prorennin observed early in cycles of conception.¹⁷⁸

Functional Abnormalities of the Corpus Luteum of Early Pregnancy

Sporadic and recurrent spontaneous abortions have been attributed to deficient function of the corpus luteum,^{77,179,180,181} but the role of this mechanism remains conjectural because the diagnosis of luteal-phase defect is imprecise and controversial,^65,182 and it is made in nonconceptive cycles.

Successful pregnancies in women with abetalipoproteinemia, in whom progesterone levels are low, would contradict the validity of defective luteal function as a cause of early pregnancy loss²⁶; progesterone levels in subjects continuing pregnancy after luteectomy in the series of Csapo and coworkers¹⁴⁹ and in women with normal pregnancies carefully studied at rest¹⁶² would suggest that levels of progesterone less than 10 ng/mL may not be abortifacient.¹⁷⁹ Diagnosis and treatment of luteal defect as a cause of abortion should be made with caution pending verification of valid physiologic and diagnostic thresholds for progesterone levels in early pregnancy.^181,183,184 Progesterone supplementation in the first trimester of pregnancy in women with a history of recurrent abortion or with threatened abortion may be reasonable, although not validated by study, when all three of the following are true: (1) normal ultrasonic landmarks for gestational age, (2) normal and normally rising levels of hCG, and (3) progesterone levels less than 10 ng/mL.

The cystic corpus luteum of pregnancy may reach a size warranting surveillance for neoplasm but generally regresses by the end of the first trimester. Pain and hemorrhage from corpora lutea of early pregnancy may mimic ectopic pregnancy and occasionally require surgical management. If luteectomy is necessary, allowance for a margin of safety for the luteoplacental shift at 7 weeks would dictate progesterone supplementation for pregnancies of 12 weeks or less.

Histology and Ultrastructure During Pregnancy

The size of the corpus luteum diminishes, owing principally to the loss of the central cavity. Luteinization of the theca layer declines, and granulosa cells are smaller. K-cells disappear, and vascularity decreases.¹⁸⁵

Secretory Physiology During Pregnancy

After the increase seen over the first weeks of gestation, luteal secretion of progesterone^144,146 and relaxin¹⁶⁴ declines. Sampling of the ovarian vessels at cesarean section and the observation that progesterone levels rise in response to hCG administration postpartum confirm continued secretion of progesterone and relaxin by the corpus luteum at term and beyond.^{42,186,187,188,189} The contribution of the corpus luteum to overall progesterone secretion is small, relative to that of the placenta; this and the dispensability of the corpus luteum after the seventh week of gestation suggest that its continuance throughout pregnancy is a functional atavism. This is in contrast to the central role of the corpus luteum in the maintenance of pregnancy in species such as rodents, in which luteolysis itself is the initiator of parturition.